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Vascular calcification (VC) is one of the major causes of cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). VC is a complex process expressing similarity to bone metabolism in onset and progression. VC in CKD is promoted by various factors not limited to hyperphosphatemia, Ca/Pi imbalance, uremic toxins, chronic inflammation, oxidative stress, and activation of multiple signaling pathways in different cell types, including vascular smooth muscle cells (VSMCs), macrophages, and endothelial cells. In the current review, we provide an in-depth analysis of the various kinds of VC, the clinical significance and available therapies, significant contributions from multiple cell types, and the associated cellular and molecular mechanisms for the VC process in the setting of CKD. Thus, we seek to highlight the key factors and cell types driving the pathology of VC in CKD in order to assist in the identification of preventative, diagnostic, and therapeutic strategies for patients burdened with this disease.
Prabhatchandra Dube; Armelle DeRiso; Mitra Patel; Dhanushya Battepati; Bella Khatib-Shahidi; Himani Sharma; Rajesh Gupta; Deepak Malhotra; Lance Dworkin; Steven Haller; David Kennedy. Vascular Calcification in Chronic Kidney Disease: Diversity in the Vessel Wall. Biomedicines 2021, 9, 404 .
AMA StylePrabhatchandra Dube, Armelle DeRiso, Mitra Patel, Dhanushya Battepati, Bella Khatib-Shahidi, Himani Sharma, Rajesh Gupta, Deepak Malhotra, Lance Dworkin, Steven Haller, David Kennedy. Vascular Calcification in Chronic Kidney Disease: Diversity in the Vessel Wall. Biomedicines. 2021; 9 (4):404.
Chicago/Turabian StylePrabhatchandra Dube; Armelle DeRiso; Mitra Patel; Dhanushya Battepati; Bella Khatib-Shahidi; Himani Sharma; Rajesh Gupta; Deepak Malhotra; Lance Dworkin; Steven Haller; David Kennedy. 2021. "Vascular Calcification in Chronic Kidney Disease: Diversity in the Vessel Wall." Biomedicines 9, no. 4: 404.
The cluster of differentiation 40 (CD40) is activated by the CD40 ligand (CD40L) in a variety of diverse cells types and regulates important processes associated with kidney disease. The CD40/CD40L signaling cascade has been comprehensively studied for its roles in immune functions, whereas the signaling axis involved in local kidney injury has only drawn attention in recent years. Clinical studies have revealed that circulating levels of soluble CD40L (sCD40L) are associated with renal function in the setting of kidney disease. Levels of the circulating CD40 receptor (sCD40), sCD40L, and local CD40 expression are tightly related to renal injury in different types of kidney disease. Additionally, various kidney cell types have been identified as non-professional antigen-presenting cells (APCs) that express CD40 on the cell membrane, which contributes to the interactions between immune cells and local kidney cells during the development of kidney injury. Although the potential for adverse CD40 signaling in kidney cells has been reported in several studies, a summary of those studies focusing on the role of CD40 signaling in the development of kidney disease is lacking. In this review, we describe the outcomes of recent studies and summarize the potential therapeutic methods for kidney disease which target CD40.
Shungang Zhang; Joshua D. Breidenbach; Benjamin H. Russell; Jerrin George; Steven T. Haller. CD40/CD40L Signaling as a Promising Therapeutic Target for the Treatment of Renal Disease. Journal of Clinical Medicine 2020, 9, 3653 .
AMA StyleShungang Zhang, Joshua D. Breidenbach, Benjamin H. Russell, Jerrin George, Steven T. Haller. CD40/CD40L Signaling as a Promising Therapeutic Target for the Treatment of Renal Disease. Journal of Clinical Medicine. 2020; 9 (11):3653.
Chicago/Turabian StyleShungang Zhang; Joshua D. Breidenbach; Benjamin H. Russell; Jerrin George; Steven T. Haller. 2020. "CD40/CD40L Signaling as a Promising Therapeutic Target for the Treatment of Renal Disease." Journal of Clinical Medicine 9, no. 11: 3653.
Viral entry mechanisms for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are an important aspect of virulence. Proposed mechanisms involve host cell membrane-bound angiotensin-converting enzyme 2 (ACE2), type II transmembrane serine proteases (TTSPs), such as transmembrane serine protease isoform 2 (TMPRSS2), lysosomal endopeptidase Cathepsin L (CTSL), subtilisin-like proprotein peptidase furin (FURIN), and even potentially membrane bound heparan sulfate proteoglycans. The distribution and expression of many of these genes across cell types representing multiple organ systems in healthy individuals has recently been demonstrated. However, comorbidities such as diabetes and cardiovascular disease are highly prevalent in patients with Coronavirus Disease 2019 (COVID-19) and are associated with worse outcomes. Whether these conditions contribute directly to SARS-CoV-2 virulence remains unclear. Here, we show that the expression levels of ACE2, TMPRSS2 and other viral entry-related genes, as well as potential downstream effector genes such as bradykinin receptors, are modulated in the target organs of select disease states. In tissues, such as the heart, which normally express ACE2 but minimal TMPRSS2, we found that TMPRSS2 as well as other TTSPs are elevated in individuals with comorbidities compared to healthy individuals. Additionally, we found the increased expression of viral entry-related genes in the settings of hypertension, cancer, or smoking across target organ systems. Our results demonstrate that common comorbidities may contribute directly to SARS-CoV-2 virulence and we suggest new therapeutic targets to improve outcomes in vulnerable patient populations.
Joshua Breidenbach; Prabhatchandra Dube; Subhanwita Ghosh; Belal Abdullah; Nikolai Modyanov; Deepak Malhotra; Lance Dworkin; Steven Haller; David Kennedy. Impact of Comorbidities on SARS-CoV-2 Viral Entry-Related Genes. Journal of Personalized Medicine 2020, 10, 146 .
AMA StyleJoshua Breidenbach, Prabhatchandra Dube, Subhanwita Ghosh, Belal Abdullah, Nikolai Modyanov, Deepak Malhotra, Lance Dworkin, Steven Haller, David Kennedy. Impact of Comorbidities on SARS-CoV-2 Viral Entry-Related Genes. Journal of Personalized Medicine. 2020; 10 (4):146.
Chicago/Turabian StyleJoshua Breidenbach; Prabhatchandra Dube; Subhanwita Ghosh; Belal Abdullah; Nikolai Modyanov; Deepak Malhotra; Lance Dworkin; Steven Haller; David Kennedy. 2020. "Impact of Comorbidities on SARS-CoV-2 Viral Entry-Related Genes." Journal of Personalized Medicine 10, no. 4: 146.
Harmful algal blooms (HAB) have become a major health concern worldwide, not just to humans that consume and recreate on contaminated waters, but also to the fauna that inhabit the environments surrounding affected areas. HABs contain heterotrophic bacteria, cyanobacterial lipopolysaccharide, and cyanobacterial toxins such as microcystins, that can cause severe toxicity in many aquatic species as well as bioaccumulation within various organs. Thus, the possibility of trophic transference of this toxin through the food chain has potentially important health implications for other organisms in the related food web. While some species have developed adaptions to attenuate the toxic effects of HAB toxins, there are still numerous species that remain vulnerable, including Lithobates catesbeiana (American bullfrog) tadpoles. In the current study we demonstrate that acute, short-term exposure of tadpoles to HAB toxins containing 1 µg/L (1 nmol/L) of total microcystins for only 7 days results in significant liver and intestinal toxicity within tadpoles. Exposed tadpoles had increased intestinal diameter, decreased intestinal fold heights, and a constant number of intestinal folds, indicating pathological intestinal distension, similar to what is seen in various disease processes, such as toxic megacolon. HAB-toxin-exposed tadpoles also demonstrated hepatocyte hypertrophy with increased hepatocyte binucleation consistent with carcinogenic and oxidative processes within the liver. Both livers and intestines of HAB-toxin-exposed tadpoles demonstrated significant increases in protein carbonylation consistent with oxidative stress and damage. These findings demonstrate that short-term exposure to HAB toxins, including microcystins, can have significant adverse effects in amphibian populations. This acute, short-term toxicity highlights the need to evaluate the influence HAB toxins may have on other vulnerable species within the food web and how those may ultimately also impact human health.
Robin C. Su; Casey M. Meyers; Emily A. Warner; Jessica A. Garcia; Jeanine M. Refsnider; Apurva Lad; Joshua D. Breidenbach; Nikolai Modyanov; Deepak Malhotra; Steven T. Haller; David J. Kennedy. Harmful Algal Bloom Toxicity in Lithobates catesbeiana Tadpoles. Toxins 2020, 12, 378 .
AMA StyleRobin C. Su, Casey M. Meyers, Emily A. Warner, Jessica A. Garcia, Jeanine M. Refsnider, Apurva Lad, Joshua D. Breidenbach, Nikolai Modyanov, Deepak Malhotra, Steven T. Haller, David J. Kennedy. Harmful Algal Bloom Toxicity in Lithobates catesbeiana Tadpoles. Toxins. 2020; 12 (6):378.
Chicago/Turabian StyleRobin C. Su; Casey M. Meyers; Emily A. Warner; Jessica A. Garcia; Jeanine M. Refsnider; Apurva Lad; Joshua D. Breidenbach; Nikolai Modyanov; Deepak Malhotra; Steven T. Haller; David J. Kennedy. 2020. "Harmful Algal Bloom Toxicity in Lithobates catesbeiana Tadpoles." Toxins 12, no. 6: 378.
Inflammatory Bowel Disease (IBD) is one of the most common gastrointestinal (GI) disorders around the world, and includes diagnoses such as Crohn’s disease and ulcerative colitis. The etiology of IBD is influenced by genetic and environmental factors. One environmental perturbagen that is not well studied within the intestines is microcystin-leucine arginine (MC-LR), which is a toxin produced by cyanobacteria in freshwater environments around the world. We recently reported that MC-LR has limited effects within the intestines of healthy mice, yet interestingly has significant toxicity within the intestines of mice with pre-existing colitis induced by dextran sulfate sodium (DSS). MC-LR was found to prolong DSS-induced weight loss, prolong DSS-induced bloody stools, exacerbate DSS-induced colonic shortening, exacerbate DSS-induced colonic ulceration, and exacerbate DSS-induced inflammatory cytokine upregulation. In addition, we previously reported a significant increase in expression of the pro-inflammatory receptor CD40 in the colons of these mice, along with downstream products of CD40 activation, including plasminogen activator inhibitor-1 (PAI-1) and monocyte chemoattractant protein-1 (MCP-1). In the current study, we demonstrate that knocking out CD40 attenuates the effects of MC-LR in mice with pre-existing colitis by decreasing the severity of weight loss, allowing a full recovery in bloody stools, preventing the exacerbation of colonic shortening, preventing the exacerbation of colonic ulceration, and preventing the upregulation of the pro-inflammatory and pro-fibrotic cytokines IL-1β, MCP-1, and PAI-1. We also demonstrate the promising efficacy of a CD40 receptor blocking peptide to ameliorate the effects of MC-LR exposure in a proof-of-concept study. Our findings suggest for the first time that MC-LR acts through a CD40-dependent mechanism to exacerbate colitis.
Robin C. Su; Emily A. Warner; Joshua D. Breidenbach; Apurva Lad; Thomas M. Blomquist; Andrew L. Kleinhenz; Nikolai Modyanov; Deepak Malhotra; David J. Kennedy; Steven T. Haller. CD40 Receptor Knockout Protects against Microcystin-LR (MC-LR) Prolongation and Exacerbation of Dextran Sulfate Sodium (DSS)-Induced Colitis. Biomedicines 2020, 8, 149 .
AMA StyleRobin C. Su, Emily A. Warner, Joshua D. Breidenbach, Apurva Lad, Thomas M. Blomquist, Andrew L. Kleinhenz, Nikolai Modyanov, Deepak Malhotra, David J. Kennedy, Steven T. Haller. CD40 Receptor Knockout Protects against Microcystin-LR (MC-LR) Prolongation and Exacerbation of Dextran Sulfate Sodium (DSS)-Induced Colitis. Biomedicines. 2020; 8 (6):149.
Chicago/Turabian StyleRobin C. Su; Emily A. Warner; Joshua D. Breidenbach; Apurva Lad; Thomas M. Blomquist; Andrew L. Kleinhenz; Nikolai Modyanov; Deepak Malhotra; David J. Kennedy; Steven T. Haller. 2020. "CD40 Receptor Knockout Protects against Microcystin-LR (MC-LR) Prolongation and Exacerbation of Dextran Sulfate Sodium (DSS)-Induced Colitis." Biomedicines 8, no. 6: 149.
Viral entry mechanisms for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are an important aspect of virulence. Proposed mechanisms involve host cell membrane-bound angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine proteases (TTSPs), such as transmembrane serine protease isoform 2 (TMPRSS2). The distribution of expression of these genes across cell types representing multiple organ systems in healthy individuals has been recently demonstrated. However, comorbidities such as diabetes and cardiovascular disease are highly prevalent in patients with Coronavirus Disease 2019 (COVID-19) and associated with worse outcomes. Whether these conditions contribute directly to SARS-CoV-2 virulence remain unclear. Here we show that the expression levels of ACE2, TMPRSS2 and other viral entry-related genes are modulated in target organs of select disease states. In tissues such as heart, which normally express ACE2 but minimal TMPRSS2, we found that TMPRSS2 as well as other TTSPs are elevated in individuals with comorbidities vs healthy individuals. Additionally, we found increased expression of viral entry-related genes in the settings of hypertension, cancer or smoking across target organ systems. Our results demonstrate that common comorbidities may contribute directly to SARS-CoV-2 virulence and suggest new therapeutic targets to improve outcomes in vulnerable patient populations.
Joshua D. Breidenbach; Prabhatchandra Dube; Subhanwita Ghosh; Nikolai N. Modyanov; Deepak Malhotra; Lance D. Dworkin; Steven T. Haller; David J. Kennedy. Impact of Comorbidities on SARS-CoV-2 Viral Entry-Related Genes. 2020, 1 .
AMA StyleJoshua D. Breidenbach, Prabhatchandra Dube, Subhanwita Ghosh, Nikolai N. Modyanov, Deepak Malhotra, Lance D. Dworkin, Steven T. Haller, David J. Kennedy. Impact of Comorbidities on SARS-CoV-2 Viral Entry-Related Genes. . 2020; ():1.
Chicago/Turabian StyleJoshua D. Breidenbach; Prabhatchandra Dube; Subhanwita Ghosh; Nikolai N. Modyanov; Deepak Malhotra; Lance D. Dworkin; Steven T. Haller; David J. Kennedy. 2020. "Impact of Comorbidities on SARS-CoV-2 Viral Entry-Related Genes." , no. : 1.
Microcystin-leucine arginine (MC-LR) is a potent liver toxin produced by freshwater cyanobacteria, also known as blue-green algae. While harmful algal blooms are increasing in frequency and severity worldwide, there is still no established method for the diagnosis and assessment of MC-LR induced liver damage. The guidelines for MC-LR safe exposure limits have been previously established based on healthy animal studies, however we have previously demonstrated that pre-existing non-alcoholic fatty liver disease (NAFLD) increases susceptiblity to the hepatotoxic effects of MC-LR. In this study, we sought to investigate the suitability of clinically used biomarkers of liver injury, specifically alanine aminotransferase (ALT) and alkaline phosphatase (ALP), as potential diagnostic tools for liver damage induced by chronic low dose administration of MC-LR in the setting of pre-existing NAFLD. In our Leprdb/J mouse model of NAFLD, we found that while MC-LR induced significant histopathologic damage in the setting of NAFLD, gene expression of ALT and ALP failed to increase with MC-LR exposure. Serum ALT and ALP also failed to increase with MC-LR exposure, except for a moderate increase in ALP with the highest dose of MC-LR used (100 μg/kg). In HepG2 human liver epithelial cells, we observed that increasing MC-LR exposure levels do not lead to an increase in ALT or ALP gene expression, intracellular enzyme activity, or extracellular activity, despite a significant increase in MC-LR induced cytotoxicity. These findings demonstrate that ALT and ALP may be unsuitable as diagnostic biomarkers for MC-LR induced liver damage.
Robin C. Su; Apurva Lad; Joshua D. Breidenbach; Andrew L. Kleinhenz; Nikolai Modyanov; Deepak Malhotra; Steven T. Haller; David J. Kennedy. Assessment of diagnostic biomarkers of liver injury in the setting of microcystin-LR (MC-LR) hepatotoxicity. Chemosphere 2020, 257, 127111 .
AMA StyleRobin C. Su, Apurva Lad, Joshua D. Breidenbach, Andrew L. Kleinhenz, Nikolai Modyanov, Deepak Malhotra, Steven T. Haller, David J. Kennedy. Assessment of diagnostic biomarkers of liver injury in the setting of microcystin-LR (MC-LR) hepatotoxicity. Chemosphere. 2020; 257 ():127111.
Chicago/Turabian StyleRobin C. Su; Apurva Lad; Joshua D. Breidenbach; Andrew L. Kleinhenz; Nikolai Modyanov; Deepak Malhotra; Steven T. Haller; David J. Kennedy. 2020. "Assessment of diagnostic biomarkers of liver injury in the setting of microcystin-LR (MC-LR) hepatotoxicity." Chemosphere 257, no. : 127111.
A method was developed to extract and quantify microcystins (MCs) from mouse liver with limits of quantification (LOQs) lower than previously reported. MCs were extracted from 40-mg liver samples using 85:15 (v:v) CH3CN:H2O containing 200 mM ZnSO4 and 1% formic acid. Solid-phase extraction with a C18 cartridge was used for sample cleanup. MCs were detected and quantified using HPLC-orbitrap-MS with simultaneous MS/MS detection of the 135.08 m/z fragment from the conserved Adda amino acid for structural confirmation. The method was used to extract six MCs (MC-LR, MC-RR, MC-YR, MC-LA, MC-LF, and MC-LW) from spiked liver tissue and the MC-LR cysteine adduct (MC-LR-Cys) created by the glutathione detoxification pathway. Matrix-matched internal standard calibration curves were constructed for each MC (R2 ≥ 0.993), with LOQs between 0.25 ng per g of liver tissue (ng/g) and 0.75 ng/g for MC-LR, MC-RR, MC-YR, MC-LA, and MC-LR-Cys, and 2.5 ng/g for MC-LF and MC-LW. The protocol was applied to extract and quantify MC-LR and MC-LR-Cys from the liver of mice that had been gavaged with 50 µg or 100 µg of MC-LR per kg bodyweight and were euthanized 2 h, 4 h, or 48 h after final gavage. C57Bl/6J (wild type, control) and Leprdb/J (experiment) mice were used as a model to study non-alcoholic fatty liver disease. The Leprdb/J mice were relatively inefficient in metabolizing MC-LR into MC-LR-Cys, which is an important defense mechanism against MC-LR exposure. Trends were also observed as a function of MC-LR gavage amount and time between final MC-LR gavage and euthanasia/organ harvest.
David Baliu-Rodriguez; Daria Kucheriavaia; Dilrukshika S. W. Palagama; Apurva Lad; Grace M. O’Neill; Johnna A. Birbeck; David J. Kennedy; Steven T. Haller; Judy A. Westrick; Dragan Isailovic. Development and Application of Extraction Methods for LC-MS Quantification of Microcystins in Liver Tissue. Toxins 2020, 12, 263 .
AMA StyleDavid Baliu-Rodriguez, Daria Kucheriavaia, Dilrukshika S. W. Palagama, Apurva Lad, Grace M. O’Neill, Johnna A. Birbeck, David J. Kennedy, Steven T. Haller, Judy A. Westrick, Dragan Isailovic. Development and Application of Extraction Methods for LC-MS Quantification of Microcystins in Liver Tissue. Toxins. 2020; 12 (4):263.
Chicago/Turabian StyleDavid Baliu-Rodriguez; Daria Kucheriavaia; Dilrukshika S. W. Palagama; Apurva Lad; Grace M. O’Neill; Johnna A. Birbeck; David J. Kennedy; Steven T. Haller; Judy A. Westrick; Dragan Isailovic. 2020. "Development and Application of Extraction Methods for LC-MS Quantification of Microcystins in Liver Tissue." Toxins 12, no. 4: 263.
Background Renal artery stenosis is a common cause of renal ischemia, contributing to the development of chronic kidney disease. To investigate the role of local CD 40 expression in renal artery stenosis, Goldblatt 2‐kidney 1‐clip surgery was performed on hypertensive Dahl salt‐sensitive rats (S rats) and genetically modified S rats in which CD 40 function is abolished ( Cd40 mutant ). Methods and Results Four weeks following the 2‐kidney 1‐clip procedure, Cd40 mutant rats demonstrated significantly reduced blood pressure and renal fibrosis in the ischemic kidneys compared with S rat controls. Similarly, disruption of Cd40 resulted in reduced 24‐hour urinary protein excretion in Cd40 mutant rats versus S rat controls (46.2±1.9 versus 118.4±5.3 mg/24 h; P <0.01), as well as protection from oxidative stress, as indicated by increased paraoxonase activity in Cd40 mutant rats versus S rat controls ( P <0.01). Ischemic kidneys from Cd40 mutant rats demonstrated a significant decrease in gene expression of the profibrotic mediator, plasminogen activator inhibitor‐1 ( P <0.05), and the proinflammatory mediators, C‐C motif chemokine ligand 19 ( P <0.01), C‐X‐C Motif Chemokine Ligand 9 ( P <0.01), and interleukin‐6 receptor ( P <0.001), compared with S rat ischemic kidneys, as assessed by quantitative PCR assay. Reciprocal renal transplantation documented that CD 40 exclusively expressed in the kidney contributes to ischemia‐induced renal fibrosis. Furthermore, human CD 40‐knockout proximal tubule epithelial cells suggested that suppression of CD 40 signaling significantly inhibited expression of proinflammatory and ‐fibrotic genes. Conclusions Taken together, our data suggest that activation of CD 40 induces a significant proinflammatory and ‐fibrotic response and represents an attractive therapeutic target for treatment of ischemic renal disease.
Shungang Zhang; Joshua D. Breidenbach; Fatimah K. Khalaf; Prabhatchandra R. Dube; Chrysan J. Mohammed; Apurva Lad; Stanislaw Stepkowski; Terry D. Hinds; Sivarajan Kumarasamy; Andrew Kleinhenz; Jiang Tian; Deepak Malhotra; David J. Kennedy; Christopher J. Cooper; Steven T. Haller. Renal Fibrosis Is Significantly Attenuated Following Targeted Disruption of Cd40 in Experimental Renal Ischemia. Journal of the American Heart Association 2020, 9, e014072 .
AMA StyleShungang Zhang, Joshua D. Breidenbach, Fatimah K. Khalaf, Prabhatchandra R. Dube, Chrysan J. Mohammed, Apurva Lad, Stanislaw Stepkowski, Terry D. Hinds, Sivarajan Kumarasamy, Andrew Kleinhenz, Jiang Tian, Deepak Malhotra, David J. Kennedy, Christopher J. Cooper, Steven T. Haller. Renal Fibrosis Is Significantly Attenuated Following Targeted Disruption of Cd40 in Experimental Renal Ischemia. Journal of the American Heart Association. 2020; 9 (7):e014072.
Chicago/Turabian StyleShungang Zhang; Joshua D. Breidenbach; Fatimah K. Khalaf; Prabhatchandra R. Dube; Chrysan J. Mohammed; Apurva Lad; Stanislaw Stepkowski; Terry D. Hinds; Sivarajan Kumarasamy; Andrew Kleinhenz; Jiang Tian; Deepak Malhotra; David J. Kennedy; Christopher J. Cooper; Steven T. Haller. 2020. "Renal Fibrosis Is Significantly Attenuated Following Targeted Disruption of Cd40 in Experimental Renal Ischemia." Journal of the American Heart Association 9, no. 7: e014072.
Non-alcoholic fatty liver disease (NAFLD) is a growing global health concern. With a propensity to progress towards non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma, NAFLD is an important link amongst a multitude of comorbidities including obesity, diabetes, and cardiovascular and kidney disease. As several in vivo models of hyperglycemia and NAFLD are employed to investigate the pathophysiology of this disease process, we aimed to characterize an in vitro model of hyperglycemia that was amenable to address molecular mechanisms and therapeutic targets at the cellular level. Utilizing hyperglycemic cell culturing conditions, we induced steatosis within a human hepatocyte cell line (HepG2 cells), as confirmed by electron microscopy. The deposition and accumulation of lipids within hyperglycemic HepG2 cells is significantly greater than in normoglycemic cells, as visualized and quantified by Nile red staining. Alanine aminotransferase (ALT) and alkaline phosphatase (ALP), diagnostic biomarkers for liver damage and disease, were found to be upregulated in hyperglycemic HepG2 cells as compared with normoglycemic cells. Suppression of CEACAM1, GLUT2, and PON1, and elevation of CD36, PCK1, and G6PK were also found to be characteristic in hyperglycemic HepG2 cells compared with normoglycemic cells, suggesting insulin resistance and NAFLD. These in vitro findings mirror the characteristic genetic and phenotypic profile seen in Leprdb/J mice, a well-established in vivo model of NAFLD. In conclusion, we characterize an in vitro model displaying several key genetic and phenotypic characteristics in common with NAFLD that may assist future studies in addressing the molecular mechanisms and therapeutic targets to combat this disease.
Robin C. Su; Apurva Lad; Joshua D. Breidenbach; Thomas M. Blomquist; William T. Gunning; Prabhatchandra Dube; Andrew L. Kleinhenz; Deepak Malhotra; Steven T. Haller; David J. Kennedy. Hyperglycemia induces key genetic and phenotypic changes in human liver epithelial HepG2 cells which parallel the Leprdb/J mouse model of non-alcoholic fatty liver disease (NAFLD). PLOS ONE 2019, 14, e0225604 .
AMA StyleRobin C. Su, Apurva Lad, Joshua D. Breidenbach, Thomas M. Blomquist, William T. Gunning, Prabhatchandra Dube, Andrew L. Kleinhenz, Deepak Malhotra, Steven T. Haller, David J. Kennedy. Hyperglycemia induces key genetic and phenotypic changes in human liver epithelial HepG2 cells which parallel the Leprdb/J mouse model of non-alcoholic fatty liver disease (NAFLD). PLOS ONE. 2019; 14 (12):e0225604.
Chicago/Turabian StyleRobin C. Su; Apurva Lad; Joshua D. Breidenbach; Thomas M. Blomquist; William T. Gunning; Prabhatchandra Dube; Andrew L. Kleinhenz; Deepak Malhotra; Steven T. Haller; David J. Kennedy. 2019. "Hyperglycemia induces key genetic and phenotypic changes in human liver epithelial HepG2 cells which parallel the Leprdb/J mouse model of non-alcoholic fatty liver disease (NAFLD)." PLOS ONE 14, no. 12: e0225604.
Microcystins are potent hepatotoxins that have become a global health concern in recent years. Their actions in at-risk populations with pre-existing liver disease is unknown. We tested the hypothesis that the No Observed Adverse Effect Level (NOAEL) of Microcystin-LR (MC-LR) established in healthy mice would cause exacerbation of hepatic injury in a murine model (Leprdb/J) of Non-alcoholic Fatty Liver Disease (NAFLD). Ten-week-old male Leprdb/J mice were gavaged with 50 μg/kg, 100 μg/kg MC-LR or vehicle every 48 h for 4 weeks (n = 15–17 mice/group). Early mortality was observed in both the 50 μg/kg (1/17, 6%), and 100 μg/kg (3/17, 18%) MC-LR exposed mice. MC-LR exposure resulted in significant increases in circulating alkaline phosphatase levels, and histopathological markers of hepatic injury as well as significant upregulation of genes associated with hepatotoxicity, necrosis, nongenotoxic hepatocarcinogenicity and oxidative stress response. In addition, we observed exposure dependent changes in protein phosphorylation sites in pathways involved in inflammation, immune function, and response to oxidative stress. These results demonstrate that exposure to MC-LR at levels that are below the NOAEL established in healthy animals results in significant exacerbation of hepatic injury that is accompanied by genetic and phosphoproteomic dysregulation in key signaling pathways in the livers of NAFLD mice.
Apurva Lad; Robin C. Su; Joshua D. Breidenbach; Paul M. Stemmer; Nicholas J. Carruthers; Nayeli K. Sanchez; Fatimah K. Khalaf; Shungang Zhang; Andrew L. Kleinhenz; Prabhatchandra Dube; Chrysan J. Mohammed; Judy A. Westrick; Erin L. Crawford; Dilrukshika Palagama; David Baliu-Rodriguez; Dragan Isailovic; Bruce Levison; Nikolai Modyanov; Amira F. Gohara; Deepak Malhotra; Steven T. Haller; David J. Kennedy. Chronic Low Dose Oral Exposure to Microcystin-LR Exacerbates Hepatic Injury in a Murine Model of Non-Alcoholic Fatty Liver Disease. Toxins 2019, 11, 486 .
AMA StyleApurva Lad, Robin C. Su, Joshua D. Breidenbach, Paul M. Stemmer, Nicholas J. Carruthers, Nayeli K. Sanchez, Fatimah K. Khalaf, Shungang Zhang, Andrew L. Kleinhenz, Prabhatchandra Dube, Chrysan J. Mohammed, Judy A. Westrick, Erin L. Crawford, Dilrukshika Palagama, David Baliu-Rodriguez, Dragan Isailovic, Bruce Levison, Nikolai Modyanov, Amira F. Gohara, Deepak Malhotra, Steven T. Haller, David J. Kennedy. Chronic Low Dose Oral Exposure to Microcystin-LR Exacerbates Hepatic Injury in a Murine Model of Non-Alcoholic Fatty Liver Disease. Toxins. 2019; 11 (9):486.
Chicago/Turabian StyleApurva Lad; Robin C. Su; Joshua D. Breidenbach; Paul M. Stemmer; Nicholas J. Carruthers; Nayeli K. Sanchez; Fatimah K. Khalaf; Shungang Zhang; Andrew L. Kleinhenz; Prabhatchandra Dube; Chrysan J. Mohammed; Judy A. Westrick; Erin L. Crawford; Dilrukshika Palagama; David Baliu-Rodriguez; Dragan Isailovic; Bruce Levison; Nikolai Modyanov; Amira F. Gohara; Deepak Malhotra; Steven T. Haller; David J. Kennedy. 2019. "Chronic Low Dose Oral Exposure to Microcystin-LR Exacerbates Hepatic Injury in a Murine Model of Non-Alcoholic Fatty Liver Disease." Toxins 11, no. 9: 486.
The burden of cardiovascular disease and death in chronic kidney disease (CKD) outpaces that of the other diseases and is not adequately described by traditional risk factors alone. Diminished activity of paraoxonase (PON)-1 is associated with increased oxidant stress, a common feature underlying the pathogenesis of CKD. We aimed to assess the prognostic value of circulating PON-1 protein and PON lactonase activity on adverse clinical outcomes across various stages and etiologies of CKD. Circulating PON-1 protein levels and PON lactonase activity were measured simultaneously in patients with CKD as well as a cohort of apparently healthy non-CKD subjects. Both circulating PON-1 protein levels and PON lactonase activity were significantly lower in CKD patients compared to the non-CKD subjects. Similarly, across all stages of CKD, circulating PON-1 protein and PON lactonase activity were significantly lower in patients with CKD compared to the non-CKD controls. Circulating PON lactonase activity, but not protein levels, predicted future adverse clinical outcomes, even after adjustment for traditional risk factors. The combination of lower circulating protein levels and higher activity within the CKD subjects were associated with the best survival outcomes. These findings demonstrate that diminished circulating PON lactonase activity, but not protein levels, predicts higher risk of future adverse clinical outcomes in patients with CKD.
Chrysan J. Mohammed; Yanmei Xie; Pamela S. Brewster; Subhanwita Ghosh; Prabhatchandra Dube; Tiana Sarsour; Andrew L. Kleinhenz; Erin L. Crawford; Deepak Malhotra; Richard W. James; Philip A. Kalra; Steven T. Haller; David J. Kennedy. Circulating Lactonase Activity but Not Protein Level of PON-1 Predicts Adverse Outcomes in Subjects with Chronic Kidney Disease. Journal of Clinical Medicine 2019, 8, 1034 .
AMA StyleChrysan J. Mohammed, Yanmei Xie, Pamela S. Brewster, Subhanwita Ghosh, Prabhatchandra Dube, Tiana Sarsour, Andrew L. Kleinhenz, Erin L. Crawford, Deepak Malhotra, Richard W. James, Philip A. Kalra, Steven T. Haller, David J. Kennedy. Circulating Lactonase Activity but Not Protein Level of PON-1 Predicts Adverse Outcomes in Subjects with Chronic Kidney Disease. Journal of Clinical Medicine. 2019; 8 (7):1034.
Chicago/Turabian StyleChrysan J. Mohammed; Yanmei Xie; Pamela S. Brewster; Subhanwita Ghosh; Prabhatchandra Dube; Tiana Sarsour; Andrew L. Kleinhenz; Erin L. Crawford; Deepak Malhotra; Richard W. James; Philip A. Kalra; Steven T. Haller; David J. Kennedy. 2019. "Circulating Lactonase Activity but Not Protein Level of PON-1 Predicts Adverse Outcomes in Subjects with Chronic Kidney Disease." Journal of Clinical Medicine 8, no. 7: 1034.
Inflammatory Bowel Disease (IBD) represents a collection of gastrointestinal disorders resulting from genetic and environmental factors. Microcystin-leucine arginine (MC-LR) is a toxin produced by cyanobacteria during algal blooms and demonstrates bioaccumulation in the intestinal tract following ingestion. Little is known about the impact of MC-LR ingestion in individuals with IBD. In this study, we sought to investigate MC-LR's effects in a dextran sulfate sodium (DSS)-induced colitis model. Mice were separated into four groups: (a) water only (control), (b) DSS followed by water (DSS), (c) water followed by MC-LR (MC-LR), and (d) DSS followed by MC-LR (DSS + MC-LR). DSS resulted in weight loss, splenomegaly, and severe colitis marked by transmural acute inflammation, ulceration, shortened colon length, and bloody stools. DSS + MC-LR mice experienced prolonged weight loss and bloody stools, increased ulceration of colonic mucosa, and shorter colon length as compared with DSS mice. DSS + MC-LR also resulted in greater increases in pro-inflammatory transcripts within colonic tissue (TNF-α, IL-1β, CD40, MCP-1) and the pro-fibrotic marker, PAI-1, as compared to DSS-only ingestion. These findings demonstrate that MC-LR exposure not only prolongs, but also worsens the severity of pre-existing colitis, strengthening evidence of MC-LR as an under-recognized environmental toxin in vulnerable populations, such as those with IBD.
Robin C. Su; Thomas M. Blomquist; Andrew L. Kleinhenz; Fatimah K. Khalaf; Prabhatchandra Dube; Apurva Lad; Joshua D. Breidenbach; Chrysan J. Mohammed; Shungang Zhang; Caitlin E. Baum; Deepak Malhotra; David J. Kennedy; Steven T. Haller. Exposure to the Harmful Algal Bloom (HAB) Toxin Microcystin-LR (MC-LR) Prolongs and Increases Severity of Dextran Sulfate Sodium (DSS)-Induced Colitis. Toxins 2019, 11, 371 .
AMA StyleRobin C. Su, Thomas M. Blomquist, Andrew L. Kleinhenz, Fatimah K. Khalaf, Prabhatchandra Dube, Apurva Lad, Joshua D. Breidenbach, Chrysan J. Mohammed, Shungang Zhang, Caitlin E. Baum, Deepak Malhotra, David J. Kennedy, Steven T. Haller. Exposure to the Harmful Algal Bloom (HAB) Toxin Microcystin-LR (MC-LR) Prolongs and Increases Severity of Dextran Sulfate Sodium (DSS)-Induced Colitis. Toxins. 2019; 11 (6):371.
Chicago/Turabian StyleRobin C. Su; Thomas M. Blomquist; Andrew L. Kleinhenz; Fatimah K. Khalaf; Prabhatchandra Dube; Apurva Lad; Joshua D. Breidenbach; Chrysan J. Mohammed; Shungang Zhang; Caitlin E. Baum; Deepak Malhotra; David J. Kennedy; Steven T. Haller. 2019. "Exposure to the Harmful Algal Bloom (HAB) Toxin Microcystin-LR (MC-LR) Prolongs and Increases Severity of Dextran Sulfate Sodium (DSS)-Induced Colitis." Toxins 11, no. 6: 371.
In 1972 Neal Bricker presented the “trade-off” hypothesis in which he detailed the role of physiological adaptation processes in mediating some of the pathophysiology associated with declines in renal function. In the late 1990’s Xie and Askari published seminal studies indicating that the Na+/K+-ATPase (NKA) was not only an ion pump, but also a signal transducer that interacts with several signaling partners. Since this discovery, numerous studies from multiple laboratories have shown that the NKA is a central player in mediating some of these long-term “trade-offs” of the physiological adaptation processes which Bricker originally proposed in the 1970’s. In fact, NKA ligands such as cardiotonic steroids (CTS), have been shown to signal through NKA, and consequently been implicated in mediating both adaptive and maladaptive responses to volume overload such as fibrosis and oxidative stress. In this review we will emphasize the role the NKA plays in this “trade-off” with respect to CTS signaling and its implication in inflammation and fibrosis in target organs including the heart, kidney, and vasculature. As inflammation and fibrosis exhibit key roles in the pathogenesis of a number of clinical disorders such as chronic kidney disease, heart failure, atherosclerosis, obesity, preeclampsia, and aging, this review will also highlight the role of newly discovered NKA signaling partners in mediating some of these conditions.
Fatimah K. Khalaf; Prabhatchandra Dube; Amal Mohamed; Jiang Tian; Deepak Malhotra; Steven T. Haller; David J. Kennedy. Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase. International Journal of Molecular Sciences 2018, 19, 2576 .
AMA StyleFatimah K. Khalaf, Prabhatchandra Dube, Amal Mohamed, Jiang Tian, Deepak Malhotra, Steven T. Haller, David J. Kennedy. Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase. International Journal of Molecular Sciences. 2018; 19 (9):2576.
Chicago/Turabian StyleFatimah K. Khalaf; Prabhatchandra Dube; Amal Mohamed; Jiang Tian; Deepak Malhotra; Steven T. Haller; David J. Kennedy. 2018. "Cardiotonic Steroids and the Sodium Trade Balance: New Insights into Trade-Off Mechanisms Mediated by the Na+/K+-ATPase." International Journal of Molecular Sciences 19, no. 9: 2576.
Hypertension is a classic example of a complex polygenic trait, impacted by quantitative trait loci (QTL) containing candidate genes thought to be responsible for blood pressure (BP) control in mammals. One such mapped locus is on rat chromosome 9, wherein the proof for a positional candidate gene, regulated endocrine-specific protein-18 ( Resp18) is currently inadequate. To ascertain the status of Resp18 as a BP QTL, a custom targeted gene disruption model of Resp18 was developed on the Dahl salt-sensitive (SS) background. As a result of this zinc-finger nuclease (ZFN)-mediated disruption, a 7 bp deletion occurred within exon 3 of the Resp18 locus. Targeted disruption of Resp18 gene locus in SS rats decreases its gene expression in both heart and kidney tissues regardless of their dietary salt level. Under a high-salt dietary regimen, both systolic and diastolic BP of Resp18mutant rats were significantly increased compared with SS rats. Resp18mutant rats demonstrated increased renal damage, as evidenced by higher proteinuria and increased renal fibrosis compared with SS rats. Furthermore, under a high-salt diet regimen, the mean survival time of Resp18mutant rats was significantly reduced compared with SS rats. These findings serve as evidence in support of Resp18 as a gene associated with the development of hypertension and renal disease.
Sivarajan Kumarasamy; Harshal Waghulde; Xi Cheng; Steven T. Haller; Blair Mell; Basrur Abhijith; Usman M. Ashraf; Ealla Atari; Bina Joe. Targeted disruption of regulated endocrine-specific protein (Resp18) in Dahl SS/Mcw rats aggravates salt-induced hypertension and renal injury. Physiological Genomics 2018, 50, 369 -375.
AMA StyleSivarajan Kumarasamy, Harshal Waghulde, Xi Cheng, Steven T. Haller, Blair Mell, Basrur Abhijith, Usman M. Ashraf, Ealla Atari, Bina Joe. Targeted disruption of regulated endocrine-specific protein (Resp18) in Dahl SS/Mcw rats aggravates salt-induced hypertension and renal injury. Physiological Genomics. 2018; 50 (5):369-375.
Chicago/Turabian StyleSivarajan Kumarasamy; Harshal Waghulde; Xi Cheng; Steven T. Haller; Blair Mell; Basrur Abhijith; Usman M. Ashraf; Ealla Atari; Bina Joe. 2018. "Targeted disruption of regulated endocrine-specific protein (Resp18) in Dahl SS/Mcw rats aggravates salt-induced hypertension and renal injury." Physiological Genomics 50, no. 5: 369-375.
Soluble CD40 ligand (sCD40L) has been implicated in the development of renal injury. The CD40 receptor exists in a soluble form, sCD40R, and has been shown to function as a competitive antagonist against CD40 activation. We analyzed whether plasma levels of sCD40L and sCD40R predict changes in renal function in an all-cause chronic kidney disease (CKD) cohort. Stratification of subjects based on sCD40L and sCD40R individually, as well as in combination, demonstrated that sCD40L was directly associated with declines in estimated glomerular filtration rate (eGFR). sCD40R was negatively associated with declines in eGFR. Baseline characteristics following stratification, including systolic blood pressure, history of diabetes mellitus or peripheral vascular disease, primary renal disease classification, and angiotensin converting enzyme inhibitor or angiotensin receptor blocker usage were not significantly different. High sCD40L and low sCD40R were both found to be independent predictors of a decline in eGFR at 1-year follow-up (−7.57%, p = 0.014; −6.39%, p = 0.044). Our data suggest that circulating levels of sCD40L and sCD40R are associated with changes in renal function in patients with CKD. The CD40 decoy receptor, sCD40R, may serve as a potential therapeutic target to attenuate renal function decline.
Jeffrey X. Xie; Helen Alderson; James Ritchie; Philip A. Kalra; Yanmei Xie; Kaili Ren; Hanh Nguyen; Tian Chen; Pamela Brewster; Rajesh Gupta; Lance D. Dworkin; Deepak Malhotra; Christopher J. Cooper; Jiang Tian; Steven T. Haller. Circulating CD40 and sCD40L Predict Changes in Renal Function in Subjects with Chronic Kidney Disease. Scientific Reports 2017, 7, 1 -7.
AMA StyleJeffrey X. Xie, Helen Alderson, James Ritchie, Philip A. Kalra, Yanmei Xie, Kaili Ren, Hanh Nguyen, Tian Chen, Pamela Brewster, Rajesh Gupta, Lance D. Dworkin, Deepak Malhotra, Christopher J. Cooper, Jiang Tian, Steven T. Haller. Circulating CD40 and sCD40L Predict Changes in Renal Function in Subjects with Chronic Kidney Disease. Scientific Reports. 2017; 7 (1):1-7.
Chicago/Turabian StyleJeffrey X. Xie; Helen Alderson; James Ritchie; Philip A. Kalra; Yanmei Xie; Kaili Ren; Hanh Nguyen; Tian Chen; Pamela Brewster; Rajesh Gupta; Lance D. Dworkin; Deepak Malhotra; Christopher J. Cooper; Jiang Tian; Steven T. Haller. 2017. "Circulating CD40 and sCD40L Predict Changes in Renal Function in Subjects with Chronic Kidney Disease." Scientific Reports 7, no. 1: 1-7.
Mark Shipeng Yu; Kun Xiang; Steven T. Haller; Christopher J. Cooper. Renal Artery Interventions. Interventional Cardiology 2016, 705 -712.
AMA StyleMark Shipeng Yu, Kun Xiang, Steven T. Haller, Christopher J. Cooper. Renal Artery Interventions. Interventional Cardiology. 2016; ():705-712.
Chicago/Turabian StyleMark Shipeng Yu; Kun Xiang; Steven T. Haller; Christopher J. Cooper. 2016. "Renal Artery Interventions." Interventional Cardiology , no. : 705-712.
Background Experimental uremic cardiomyopathy causes cardiac fibrosis and is causally related to the increased circulating levels of the cardiotonic steroid, marinobufagenin ( MBG ), which signals through Na/K‐ ATP ase. Rapamycin is an inhibitor of the serine/threonine kinase mammalian target of rapamycin (mTOR) implicated in the progression of many different forms of renal disease. Given that Na/K‐ ATP ase signaling is known to stimulate the mTOR system, we speculated that the ameliorative effects of rapamycin might influence this pathway. Methods and Results Biosynthesis of MBG by cultured human JEG ‐3 cells is initiated by CYP 27A1, which is also a target for rapamycin. It was demonstrated that 1 μmol/L of rapamycin inhibited production of MBG in human JEG ‐2 cells. Male Sprague‐Dawley rats were subjected to either partial nephrectomy ( PN x), infusion of MBG , and/or infusion of rapamycin through osmotic minipumps. PN x animals showed marked increase in plasma MBG levels (1025±60 vs 377±53 pmol/L; P <0.01), systolic blood pressure (169±1 vs 111±1 mm Hg; P <0.01), and cardiac fibrosis compared to controls. Plasma MBG levels were significantly decreased in PN x‐rapamycin animals compared to PN x (373±46 vs 1025±60 pmol/L; P <0.01), and cardiac fibrosis was substantially attenuated by rapamycin treatment. Conclusions Rapamycin treatment in combination with MBG infusion significantly attenuated cardiac fibrosis. Our results suggest that rapamycin may have a dual effect on cardiac fibrosis through (1) mTOR inhibition and (2) inhibiting MBG‐ mediated profibrotic signaling and provide support for beneficial effect of a novel therapy for uremic cardiomyopathy.
Steven T. Haller; Yanling Yan; Christopher Drummond; Joe Xie; Jiang Tian; David J. Kennedy; Victoria Y. Shilova; Zijian Xie; Jiang Liu; Christopher J. Cooper; Deepak Malhotra; Joseph I. Shapiro; Olga V. Fedorova; Alexei Bagrov. Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro‐Fibrotic Signaling. Journal of the American Heart Association 2016, 5, 1 .
AMA StyleSteven T. Haller, Yanling Yan, Christopher Drummond, Joe Xie, Jiang Tian, David J. Kennedy, Victoria Y. Shilova, Zijian Xie, Jiang Liu, Christopher J. Cooper, Deepak Malhotra, Joseph I. Shapiro, Olga V. Fedorova, Alexei Bagrov. Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro‐Fibrotic Signaling. Journal of the American Heart Association. 2016; 5 (10):1.
Chicago/Turabian StyleSteven T. Haller; Yanling Yan; Christopher Drummond; Joe Xie; Jiang Tian; David J. Kennedy; Victoria Y. Shilova; Zijian Xie; Jiang Liu; Christopher J. Cooper; Deepak Malhotra; Joseph I. Shapiro; Olga V. Fedorova; Alexei Bagrov. 2016. "Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro‐Fibrotic Signaling." Journal of the American Heart Association 5, no. 10: 1.
High blood pressure is a common cause of chronic kidney disease. Because CD40, a member of the tumor necrosis factor receptor family, has been linked to the progression of kidney disease in ischemic nephropathy, we studied the role of Cd40 in the development of hypertensive renal disease. The Cd40 gene was mutated in the Dahl S genetically hypertensive rat with renal disease by targeted-gene disruption using zinc-finger nuclease technology. These rats were then given low (0.3%) and high (2%) salt diets and compared. The resultant Cd40 mutants had significantly reduced levels of both urinary protein excretion (41.8 ± 3.1 mg/24 h vs. 103.7 ± 4.3 mg/24 h) and plasma creatinine (0.36 ± 0.05 mg/dl vs. 1.15 ± 0.19 mg/dl), with significantly higher creatinine clearance compared with the control S rats (3.04 ± 0.48 ml/min vs. 0.93 ± 0.15 ml/min), indicating renoprotection was conferred by mutation of the Cd40 locus. Furthermore, the Cd40 mutants had a significant attenuation in renal fibrosis, which persisted on the high salt diet. However, there was no difference in systolic blood pressure between the control and Cd40 mutant rats. Thus, these data serve as the first evidence for a direct link between Cd40 and hypertensive nephropathy. Hence, renal fibrosis is one of the underlying mechanisms by which Cd40 plays a crucial role in the development of hypertensive renal disease.
Steven T. Haller; Sivarajan Kumarasamy; David A. Folt; Leah Wuescher; Stanislaw Stepkowski; Manish Karamchandani; Harshal Waghulde; Blair Mell; Muhammad Chaudhry; Kyle Maxwell; Siddhi Upadhyaya; Christopher Drummond; Jiang Tian; Wanda E. Filipiak; Thom Saunders; Joseph I. Shapiro; Bina Joe; Christopher J. Cooper. Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure. Kidney International 2016, 91, 365 -374.
AMA StyleSteven T. Haller, Sivarajan Kumarasamy, David A. Folt, Leah Wuescher, Stanislaw Stepkowski, Manish Karamchandani, Harshal Waghulde, Blair Mell, Muhammad Chaudhry, Kyle Maxwell, Siddhi Upadhyaya, Christopher Drummond, Jiang Tian, Wanda E. Filipiak, Thom Saunders, Joseph I. Shapiro, Bina Joe, Christopher J. Cooper. Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure. Kidney International. 2016; 91 (2):365-374.
Chicago/Turabian StyleSteven T. Haller; Sivarajan Kumarasamy; David A. Folt; Leah Wuescher; Stanislaw Stepkowski; Manish Karamchandani; Harshal Waghulde; Blair Mell; Muhammad Chaudhry; Kyle Maxwell; Siddhi Upadhyaya; Christopher Drummond; Jiang Tian; Wanda E. Filipiak; Thom Saunders; Joseph I. Shapiro; Bina Joe; Christopher J. Cooper. 2016. "Targeted disruption of Cd40 in a genetically hypertensive rat model attenuates renal fibrosis and proteinuria, independent of blood pressure." Kidney International 91, no. 2: 365-374.
Atherosclerotic renal artery stenosis is a major cause of resistant hypertension. Cigarette smoking causes cardiovascular disease and may be associated with loss of kidney function. However, the impact of smoking on patients with atherosclerotic renal artery stenosis has not been studied. The following design and methodology was used: data from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL, NCT00081731) clinical trial was analyzed to determine the effects of smoking on the risk of cardiac and renal events and on kidney function. In all 277 out of 931 enrolled patients were smokers. The composite endpoint, blindly adjudicated by a clinical events committee, was the first occurrence of any listed clinical event: stroke, cardiovascular or renal death, myocardial infarction, hospitalization for congestive heart failure, progressive renal insufficiency, and permanent renal replacement therapy. The results indicate that smokers were much younger at enrollment than non-smokers (63.3±9.1 vs. 72.4±7.8 years; p0.05). Cox-proportional hazard analysis using age-at-event showed that patients who smoked were 2.32 (1.79, 2.98; p0.05) and estimated glomerular filtration rate (eGFR, 4.1±0.1 vs 4.0±0.1 mL/min/1.73m2, p>0.05) were not significantly different from non-smokers. In conclusion cigarette smoking increases the risk of cardiac and renal events in patients with renal artery stenosis, including cardiovascular or renal death, myocardial infarction, stroke, hospitalization for congestive heart failure, and progressive renal insufficiency.
Christopher A. Drummond; Pamela S. Brewster; Wencan He; Kaili Ren; Kaleigh L. Evans; Katherine R. Tuttle; Shpeng Yu; Taylor Dawson; Steven T. Haller; Kenneth Jamerson; Lance D. Dworkin; Donald E. Cutlip; Timothy P. Murphy; Ralph B. D'agostino; William Henrich; Joseph I. Shaprio; Christopher J. Cooper; Jiang Tian. Cigarette smoking and cardio-renal events in patients with atherosclerotic renal artery stenosis. Journal of the American Society of Hypertension 2015, 9, e53 .
AMA StyleChristopher A. Drummond, Pamela S. Brewster, Wencan He, Kaili Ren, Kaleigh L. Evans, Katherine R. Tuttle, Shpeng Yu, Taylor Dawson, Steven T. Haller, Kenneth Jamerson, Lance D. Dworkin, Donald E. Cutlip, Timothy P. Murphy, Ralph B. D'agostino, William Henrich, Joseph I. Shaprio, Christopher J. Cooper, Jiang Tian. Cigarette smoking and cardio-renal events in patients with atherosclerotic renal artery stenosis. Journal of the American Society of Hypertension. 2015; 9 (4):e53.
Chicago/Turabian StyleChristopher A. Drummond; Pamela S. Brewster; Wencan He; Kaili Ren; Kaleigh L. Evans; Katherine R. Tuttle; Shpeng Yu; Taylor Dawson; Steven T. Haller; Kenneth Jamerson; Lance D. Dworkin; Donald E. Cutlip; Timothy P. Murphy; Ralph B. D'agostino; William Henrich; Joseph I. Shaprio; Christopher J. Cooper; Jiang Tian. 2015. "Cigarette smoking and cardio-renal events in patients with atherosclerotic renal artery stenosis." Journal of the American Society of Hypertension 9, no. 4: e53.