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The goal of this study was to develop a mathematical model to simulate the actions of drugs that target SARS-CoV-2 virus infection. To accomplish that goal, we have developed a mathematical model that describes the control of a SARS-CoV-2 infection by the innate and adaptive immune components. Invasion of the virus triggers the innate immunity, whereby interferon renders some of the target cells resistant to infection, and infected cells are removed by effector cells. The adaptive immune response is represented by plasma cells and virus-specific antibodies. The model is parameterized and then validated against viral load measurements collected in COVID-19 patients. We apply the model to simulate three potential anti-SARS-CoV-2 therapies: (1) Remdesivir, a repurposed drug that has been shown to inhibit the transcription of SARS-CoV-2, (2) an alternative (hypothetical) therapy that inhibits the virus’ entry into host cells, and (3) convalescent plasma transfusion therapy. Simulation results point to the importance of early intervention, i.e., for any of the three therapies to be effective, it must be administered sufficiently early, not more than a day or two after the onset of symptoms. The model can serve as a key component in integrative platforms for rapid in silico testing of potential COVID-19 therapies and vaccines.
Mehrshad Sadria; Anita Layton. Modeling within-Host SARS-CoV-2 Infection Dynamics and Potential Treatments. Viruses 2021, 13, 1141 .
AMA StyleMehrshad Sadria, Anita Layton. Modeling within-Host SARS-CoV-2 Infection Dynamics and Potential Treatments. Viruses. 2021; 13 (6):1141.
Chicago/Turabian StyleMehrshad Sadria; Anita Layton. 2021. "Modeling within-Host SARS-CoV-2 Infection Dynamics and Potential Treatments." Viruses 13, no. 6: 1141.
Beyond the reproductive system and reproductive behaviors, men and women exhibit major differences in many organ systems, including the anatomy of the brain, the activities of the stress and immune systems, and the metabolic and cardiovascular functions. A comprehensive understanding of the impact of these sex differences on health and disease is crucial to the development of effective sex-based therapies. Mathematical modeling has the potential of facilitating and contributing to advancing the understanding of sex differences in health and disease. Indeed, explosion of mathematical models have been developed in recent decades for different aspects of human physiology and pathophysiology. This review contains a survey of sex-specific mathematical models of physiological systems, describe insights that have been revealed in those modeling studies, and discuss future opportunities.
Anita T. Layton. His and her mathematical models of physiological systems. Mathematical Biosciences 2021, 338, 108642 .
AMA StyleAnita T. Layton. His and her mathematical models of physiological systems. Mathematical Biosciences. 2021; 338 ():108642.
Chicago/Turabian StyleAnita T. Layton. 2021. "His and her mathematical models of physiological systems." Mathematical Biosciences 338, no. : 108642.
At the onset of diabetes, the kidney grows large and the glomerular filtration rate becomes abnormally high. These structural and hemodynamics changes affect kidney function and may contribute to the development of chronic kidney disease. The goal of this study is to analyze how kidney function is altered in patients with diabetes and the renal effects of an anti-hyperglyceamic therapy that inhibits the sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubules. To accomplish that goal, we have developed a computational model of kidney function in a patient with diabetes and conducted simulations to study the effects of diabetes and SGLT2 inhibition on solute and water transport along the nephrons. Simulation results indicate that diabetes-induced hyperfiltration and tubular hypertrophy enhances Na+ transport, especially along the proximal tubules and thick ascending limbs. These simulations suggest that SGLT2 inhibition may attenuate glomerular hyperfiltration by limiting Na+-glucose transport, raising luminal [Cl−] at the macula densa, restoring the tubuloglomerular feedback signal, thereby reducing single-nephron glomerular filtration rate.
Rui Hu; Anita Layton. A Computational Model of Kidney Function in a Patient with Diabetes. International Journal of Molecular Sciences 2021, 22, 5819 .
AMA StyleRui Hu, Anita Layton. A Computational Model of Kidney Function in a Patient with Diabetes. International Journal of Molecular Sciences. 2021; 22 (11):5819.
Chicago/Turabian StyleRui Hu; Anita Layton. 2021. "A Computational Model of Kidney Function in a Patient with Diabetes." International Journal of Molecular Sciences 22, no. 11: 5819.
Summary The kidneys maintain homeostasis by controlling the amount of water and electrolytes in the blood. That function is accomplished by the nephrons, which transform glomerular filtrate into urine by a transport process mediated by membrane transporters. We postulate that the distribution of renal transporters along the nephron is markedly different between men and women, as recently shown in rodents. We hypothesize that the larger abundance of a renal Na+ transport in the proximal tubules in females may also better prepare them for the fluid retention adaptations required during pregnancy and lactation. Also, kidneys play a key role in blood pressure regulation, and a popular class of anti-hypertensive medications and angiotensin converting enzymes (ACE) inhibitors have been reported to be less effective in women. Model simulations suggest that the blunted natriuretic and diuretic effects of ACE inhibition in women can be attributed, in part, to their higher distal baseline transport capacity.
Rui Hu; Alicia A. McDonough; Anita T. Layton. Sex differences in solute and water handling in the human kidney: Modeling and functional implications. iScience 2021, 24, 102667 .
AMA StyleRui Hu, Alicia A. McDonough, Anita T. Layton. Sex differences in solute and water handling in the human kidney: Modeling and functional implications. iScience. 2021; 24 (6):102667.
Chicago/Turabian StyleRui Hu; Alicia A. McDonough; Anita T. Layton. 2021. "Sex differences in solute and water handling in the human kidney: Modeling and functional implications." iScience 24, no. 6: 102667.
Background Cells adapt their metabolism and activities in response to signals from their surroundings, and this ability is essential for their survival in the face of perturbations. In tissues a deficit of these mechanisms is commonly associated with cellular aging and diseases, such as cardiovascular disease, cancer, immune system decline, and neurological pathologies. Several proteins have been identified as being able to respond directly to energy, nutrient, and growth factor levels and stress stimuli in order to mediate adaptations in the cell. In particular, mTOR, AMPK, and sirtuins are known to play an essential role in the management of metabolic stress and energy balance in mammals. Methods To understand the complex interactions of these signalling pathways and environmental signals, and how those interactions may impact lifespan and health-span, we have developed a computational model of metabolic signalling pathways. Specifically, the model includes (i) the insulin/IGF-1 pathway, which couples energy and nutrient abundance to the execution of cell growth and division, (ii) mTORC1 and the amino acid sensors such as sestrin, (iii) the Preiss-Handler and salvage pathways, which regulate the metabolism of NAD+ and the NAD+ -consuming factor SIRT1, (iv) the energy sensor AMPK, and (v) transcription factors FOXO and PGC-1α. Results The model simulates the interactions among key regulators such as AKT, mTORC1, AMPK, NAD+ , and SIRT, and predicts their dynamics. Key findings include the clinically important role of PRAS40 and diet in mTORC1 inhibition, and a potential link between SIRT1-activating compounds and premature autophagy. Moreover, the model captures the exquisite interactions of leucine, sestrin2, and arginine, and the resulting signal to the mTORC1 pathway. These results can be leveraged in the development of novel treatment of cancers and other diseases. Conclusions This study presents a state-of-the-art computational model for investigating the interactions among signaling pathways and environmental stimuli in growth, ageing, metabolism, and diseases. The model can be used as an essential component to simulate gene manipulation, therapies (e.g., rapamycin and wortmannin), calorie restrictions, and chronic stress, and assess their functional implications on longevity and ageing‐related diseases.
Mehrshad Sadria; Anita T. Layton. Interactions among mTORC, AMPK and SIRT: a computational model for cell energy balance and metabolism. Cell Communication and Signaling 2021, 19, 1 -17.
AMA StyleMehrshad Sadria, Anita T. Layton. Interactions among mTORC, AMPK and SIRT: a computational model for cell energy balance and metabolism. Cell Communication and Signaling. 2021; 19 (1):1-17.
Chicago/Turabian StyleMehrshad Sadria; Anita T. Layton. 2021. "Interactions among mTORC, AMPK and SIRT: a computational model for cell energy balance and metabolism." Cell Communication and Signaling 19, no. 1: 1-17.
The circadian clock exerts significance influence on the immune system and disruption of circadian rhythms has been linked to inflammatory pathologies. Shift workers often experience circadian misalignment as their irregular work schedules disrupt the natural light-dark cycle, which in turn can cause serious health problems associated with alterations in genetic expressions of clock genes. In particular, shift work is associated with impairment in immune function, and those alterations are sex-specific. The goal of this study is to better understand the mechanisms that explain the weakened immune system in shift workers. To achieve that goal, we have constructed a mathematical model of the mammalian pulmonary circadian clock coupled to an acute inflammation model in the male and female rats. Shift work was simulated by an 8h-phase advance of the circadian system with sex-specific modulation of clock genes. The model reproduces the clock gene expression in the lung and the immune response to various doses of lipopolysaccharide (LPS). Under normal conditions, our model predicts that a host is more sensitive to LPS at circadian time (CT) CT12 versus CT0 due to a dynamic change of Interleukin 10 (IL-10), an anti-inflammatory cytokine. We identify REV-ERB as a key modulator of IL-10 activity throughout the circadian day. The model also predicts a reversal of the times of lowest and highest sensitivity to LPS, with males and females exhibiting an exaggerated response to LPS at CT0, which is countered by a blunted immune response at CT12. Overall, females produce fewer pro-inflammatory cytokines than males, but the extent of sequelae experienced by males and females varies across the circadian day. This model can serve as an essential component in an integrative model that will yield mechanistic understanding of how shift work-mediated circadian disruptions affect the inflammatory and other physiological responses.
Stéphanie M. C. Abo; Anita T. Layton. Modeling the circadian regulation of the immune system: Sexually dimorphic effects of shift work. PLOS Computational Biology 2021, 17, e1008514 .
AMA StyleStéphanie M. C. Abo, Anita T. Layton. Modeling the circadian regulation of the immune system: Sexually dimorphic effects of shift work. PLOS Computational Biology. 2021; 17 (3):e1008514.
Chicago/Turabian StyleStéphanie M. C. Abo; Anita T. Layton. 2021. "Modeling the circadian regulation of the immune system: Sexually dimorphic effects of shift work." PLOS Computational Biology 17, no. 3: e1008514.
Besides the excretion of metabolic wastes, the kidneys regulate homeostasis of electrolytes, pH, metabolites, volume and blood pressure. Sex differences in kidney function and blood pressure have been widely described across many species. Immunoblot analysis has revealed that the kidney of a female rat is not simply a smaller version of a male kidney. Rather, male and female rat kidneys exhibit dimorphic patterns of transporter expression and salt handling, the functional implications of which have been analyzed in a series of previously published modeling studies of rat kidney function. In the present study, we extend the analysis to the human kidney: we developed sex-specific models of solute and water transport in the human kidney, and identified epithelial transport parameters, consistent with patterns found in male and female rats, that yield urine output and excretion rates consistent with known human values. The model predicts that the lower sodium hydrogen exchanger 3 (NHE3) activity in women reduces the fractional reabsorption of Na+, K+, Cl-, and water along the proximal tubule, compared to men, and that the larger load on the distal nephron can be handled by enhanced activities in key Na+ transporter such as epithelial sodium channel (ENaC) and sodium chloride cotransporter (NCC) in women. Model simulations further indicate that the larger distal transport capacity and proximal transport reserve may better prepare women for elevated demands of pregnancy and lactation. The larger distal transport capacity may also contribute to reduced efficacy of angiotensin converting enzyme inhibitors to lower blood pressure in women. Author summary The kidneys maintain homeostasis by controlling the amount of water, ions, and other substances in the blood. That function is accomplished by the nephrons, which transform glomerular filtrate into urine by an exquisite transport process mediated by a number of membrane transporters. Recently, the distribution of renal transporters along the nephron has been shown to be markedly different between male and female rodents. We postulate that similar sexual dimorphism exists between men and women, and we seek to reveal its physiological implications. We hypothesize that the larger abundance of a renal Na+ transport in the proximal tubules in females may also better prepare them for the fluid retention adaptations required during pregnancy and lactation, durint which renal and systemic hemodynamics are both drastically altered by the marked volume expansion and vasodilation. Also, kidneys play a key role in blood pressure regulation, and a popular class of anti-hypertensive medications, angiotensin converting enzymes (ACE) inhibitors, have been reported to be less effective in women. Model simulations suggest that the blunted natriuretic and diuretic effects of ACE inhibition in women can be attributed, in part, to their higher distal baseline transport capacity.
Rui Hu; Alicia A. McDonough; Anita T. Layton. Sex Differences in Solute and Water Handling in the Human Kidney: Modeling and Functional Implications. 2021, 1 .
AMA StyleRui Hu, Alicia A. McDonough, Anita T. Layton. Sex Differences in Solute and Water Handling in the Human Kidney: Modeling and Functional Implications. . 2021; ():1.
Chicago/Turabian StyleRui Hu; Alicia A. McDonough; Anita T. Layton. 2021. "Sex Differences in Solute and Water Handling in the Human Kidney: Modeling and Functional Implications." , no. : 1.
The circadian clock exerts significance influence on the immune system and disruption of circadian rhythms has been linked to inflammatory pathologies. shift workers often experience circadian misalignment as their irregular work schedules disrupt the natural sleep-wake cycle, which in turn can cause serious health problems associated with alterations in genetic expressions of clock genes. In particular, shift work is associated with impairment in immune function, and those alterations are sex-specific. The goal of this study is to better understand the mechanisms that explain the weakened immune system in shift workers. To achieve that goal, we have constructed a mathematical model of the mammalian pulmonary circadian clock coupled to an acute inflammation model. shift work was simulated by an 8h-phase advance of the circadian system with sex-specific modulation of clock genes. The model reproduces the clock gene expression in the lung and the immune response to various doses of lipopolysaccharide (LPS). Under normal conditions, our model predicts that a host is more sensitive to LPS at CT12 versus CT0 due to a change in the dynamics of IL-10. We identify REV-ERB as a key modulator of IL-10 activity throughout the circadian day. The model also predicts a reversal of the times of lowest and highest sensitivity to LPS, with males and females exhibiting an exaggerated response to LPS at circadian time (CT) 0, which is countered by a blunted immune response at CT12. Overall, females produce fewer pro-inflammatory cytokines than males, but the extent of sequelae experienced by males and females varies across the circadian day. This model can serve as an essential component in an integrative model that will yield mechanistic understanding of how shift work-mediated circadian disruptions affect the inflammatory and other physiological responses.Author summaryShift work has a negative impact on health and can lead to chronic diseases and illnesses. Under regular work schedules, rest is a night time activity and work a daytime activity. Shift work relies on irregular work schedules which disrupt the natural sleep-wake cycle. This can in turn disrupt our biological clock, called the circadian clock, a network of molecular interactions generating biochemical oscillations with a near 24-hour period. Clock genes regulate cytokines before and during infection and immune agents can also impact the clock function. We provide a mathematical model of the circadian clock in the lung coupled to an acute inflammation model to study how the disruptive effect of shift work manifests itself in males and females during inflammation. Our results show that the extent of sequelae experienced by male and female mice depends on the time of infection. The goal of this study is to provide a mechanistic insight of the dynamics involved in the interplay between these two systems.
Stéphanie M.C. Abo; Anita T. Layton. Modeling the circadian regulation of the immune system: sexually dimorphic effects of shift work. 2020, 1 .
AMA StyleStéphanie M.C. Abo, Anita T. Layton. Modeling the circadian regulation of the immune system: sexually dimorphic effects of shift work. . 2020; ():1.
Chicago/Turabian StyleStéphanie M.C. Abo; Anita T. Layton. 2020. "Modeling the circadian regulation of the immune system: sexually dimorphic effects of shift work." , no. : 1.
Acute kidney injury (AKI) diagnosis relies on plasma creatinine concentration (Crpl), a relatively insensitive, surrogate biomarker of glomerular filtration rate that increases only after significant damage befalls. However, damage in different renal structures may occur without increments in Crpl, a condition known as subclinical AKI. Thus, detection of alterations in other aspects of renal function different from glomerular filtration rate must be included in an integral diagnosis of AKI. With this aim, we adapted to and validated in rats (for preclinical research) the furosemide stress test (FST), a tubular function test hitherto performed only in humans. We also tested its sensitivity in detecting subclinical tubular alterations. In particular, we predisposed rats to AKI with 3 mg/kg cisplatin and subsequently subjected them to a triggering insult (ie, 50 mg/kg/d gentamicin for 6 days) that had no effect on nonpredisposed animals but caused an overt AKI in predisposed rats. The FST was performed immediately before adding the triggering insult. Predisposed animals showed a reduced response to the FST (namely, reduced furosemide-induced diuresis and K+ excretion), whereas nonpredisposed animals showed no alteration, compared to the controls. Computational modeling of epithelial transport of solutes and water along the nephrons applied to experimental data suggested that proximal tubule transport was only minimally reduced, the sodium-chloride symporter was upregulated by 50%, and the renal outer medullary potassium channel was downregulated by 85% in predisposed animals. In conclusion, serial coupling of the FST and computational modeling may be used to detect and localize subclinical tubular alterations.
Alfredo G. Casanova; Isabel Fuentes-Calvo; María T. Hernández-Sánchez; Miguel Quintero; Paula Toral; María T. Caballero; Carlos Martínez-Salgado; Ana I. Morales; Anita T. Layton; Nélida Eleno; Francisco J. López-Hernández. The furosemide stress test and computational modeling identify renal damage sites associated with predisposition to acute kidney injury in rats. Translational Research 2020, 231, 76 -91.
AMA StyleAlfredo G. Casanova, Isabel Fuentes-Calvo, María T. Hernández-Sánchez, Miguel Quintero, Paula Toral, María T. Caballero, Carlos Martínez-Salgado, Ana I. Morales, Anita T. Layton, Nélida Eleno, Francisco J. López-Hernández. The furosemide stress test and computational modeling identify renal damage sites associated with predisposition to acute kidney injury in rats. Translational Research. 2020; 231 ():76-91.
Chicago/Turabian StyleAlfredo G. Casanova; Isabel Fuentes-Calvo; María T. Hernández-Sánchez; Miguel Quintero; Paula Toral; María T. Caballero; Carlos Martínez-Salgado; Ana I. Morales; Anita T. Layton; Nélida Eleno; Francisco J. López-Hernández. 2020. "The furosemide stress test and computational modeling identify renal damage sites associated with predisposition to acute kidney injury in rats." Translational Research 231, no. : 76-91.
Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are frequently prescribed for a range of diseases including hypertension, proteinuric chronic kidney disease, and heart failure. There is evidence indicating that these drugs upregulate ACE2, a key component of the renin-angiotensin system (RAS) and is found on the cells of a number of tissues, including the epithelial cells in the lungs. While ACE2 has a beneficial role in many diseases such as hypertension, diabetes, and cardiovascular disease, it also serves as a receptor for both SARS-CoV and SARS-CoV-2 via binding with the spike protein of the virus, thereby allowing it entry into host cells. Thus, it has been suggested that these therapies can theoretically increase the risk of SARS- CoV-2 infection and cause more severe COVID-19. Given the success of ACEi and ARBs in cardiovascular diseases, we seek to gain insights into the implications of these medications in the pathogenesis of COVID-19. To that end, we have developed a mathematical model that represents the RAS, binding of ACE2 with SARS-CoV-2 and the subsequent cell entry, and the host’s acute inflammatory response. The model can simulate different levels of SARS-CoV-2 exposure, and represent the effect of commonly prescribed anti-hypertensive medications, ACEi and ARB, and predict tissue damage. Model simulations indicate that whether the extent of tissue damage may be exacerbated by ACEi or ARB treatment depends on a number of factors, including the level of existing inflammation, dosage, and the effect of the drugs on ACE2 protein abundance. The findings of this study can serve as the first step in the development of appropriate and more comprehensive guidelines for the prescription of ACEi and ARB in the current and future coronavirus pandemics. As we brace for the devastating impact of the COVID-19 pandemic, we must tackle a controversy on how to best minimize the risk of lethal disease among the most vulnerable. Preliminary epidemiological data show an exponential increase in disease severity and mortality among patients with cardiovascular disease and diabetes. The coronavirus enters host cells by binding to a specific enzyme “ACE2” on the cell membrane. ACE2 abundance is increased in patients with cardiovascular disease and diabetes treated with two classes of drugs: angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB). This has generated controversy regarding the approach for patients taking these drugs during the pandemic, with some advocating for discontinuing these medications, while expert opinions recommended against discontinuation, given the lack of strong evidence. Given the success of ACEi and ARBs in cardiovascular diseases, we aim to help patients and physicians weigh the overall pros and cons. To achieve that goal, we have developed a mathematical model of the invasion of the coronavirus and the host’s immune response. Model simulations indicate how much tissue damage COVID-19 induces in a patient undergoing ACEi or ARB treatment depends on a number of factors, including the level of any existing chronic inflammation, dosage, and certain drugs effects.
Mehrshad Sadria; Anita T. Layton. Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers During the COVID-19 Pandemic: A Modeling Analysis. PLOS Computational Biology 2020, 16, e1008235 .
AMA StyleMehrshad Sadria, Anita T. Layton. Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers During the COVID-19 Pandemic: A Modeling Analysis. PLOS Computational Biology. 2020; 16 (10):e1008235.
Chicago/Turabian StyleMehrshad Sadria; Anita T. Layton. 2020. "Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers During the COVID-19 Pandemic: A Modeling Analysis." PLOS Computational Biology 16, no. 10: e1008235.
Key proteins such as mTORC, AMPK, and sirtuins are known to play an essential role in the management of metabolic stress and ageing mechanisms. An impairment in these mechanisms is commonly associated with cellular ageing and degenerative diseases. To understand the complex interactions of ageing-related signalling pathways and environmental signals, and the impacts on lifespan and health-span, we developed a computational model of ageing signalling pathways. The model includes (i) the insulin/IGF-1 pathway, which couples energy and nutrient abundance to the execution of cell growth and division, (ii) mTORC1 and amino acid sensors, (iii) the Preiss-Handler and salvage pathways, which regulate the metabolism of NAD+ and the NAD+-consuming factor SIRT1, (iv) the energy sensor AMPK, and (v) transcription factors FOXO and PGC-1alpha Key findings include the clinically important role of PRAS40, sestrin2, and diet in the treatment of cancers and other diseases, and a potential link between SIRT1-activating compounds and premature autophagy. The model can be used as an essential component to simulate gene manipulation, therapies (e.g., rapamycin and wortmannin), calorie restrictions, and chronic stress, and to assess their functional implications on longevity and ageing-related diseases.
Mehrshad Sadria; Anita Layton. Interactions among mTORC, AMPK, and SIRT: A Computational Model for Cell Energy Balance and Metabolism. 2020, 1 .
AMA StyleMehrshad Sadria, Anita Layton. Interactions among mTORC, AMPK, and SIRT: A Computational Model for Cell Energy Balance and Metabolism. . 2020; ():1.
Chicago/Turabian StyleMehrshad Sadria; Anita Layton. 2020. "Interactions among mTORC, AMPK, and SIRT: A Computational Model for Cell Energy Balance and Metabolism." , no. : 1.
The goal of the present study was to investigate the functional implications of sexual dimorphism in the pattern of transporters along the rodent nephron as reported by Veiras et al. ( J Am Soc Nephrol 28: 3504–3517, 2017). To do so, we developed sex-specific computational models of water and solute transport along the superficial nephrons from male and female rat kidneys. The models account for the sex differences in the abundance of apical and basolateral transporters, single nephron glomerular filtration rate, and tubular dimensions. Model simulations predict that ~70% and 60% of filtered Na+ is reabsorbed by the proximal tubule of male and female rat kidneys, respectively. The lower fractional Na+ reabsorption in female kidneys is due primarily to their smaller transport area, lower Na+/H+ exchanger activity, and lower claudin-2 abundance, culminating in significantly larger fractional delivery of water and Na+ to the downstream nephron segments in female kidneys. Conversely, the female distal nephron exhibits a higher abundance of key Na+ transporters, including Na+-K+-Cl− cotransporters, Na+-Cl− cotransporters, and epithelial Na+ channels. The higher abundance of transporters accounts for the enhanced water and Na+ transport along the female, relative to male, distal nephron, resulting in similar urine excretion between the sexes. Consequently, in response to a saline load, the Na+ load delivered distally is greater in female rats than male rats, overwhelming transport capacity and resulting in higher natriuresis in female rats.
Rui Hu; Alicia A. McDonough; Anita T. Layton. Functional implications of the sex differences in transporter abundance along the rat nephron: modeling and analysis. American Journal of Physiology-Renal Physiology 2019, 317, F1462 -F1474.
AMA StyleRui Hu, Alicia A. McDonough, Anita T. Layton. Functional implications of the sex differences in transporter abundance along the rat nephron: modeling and analysis. American Journal of Physiology-Renal Physiology. 2019; 317 (6):F1462-F1474.
Chicago/Turabian StyleRui Hu; Alicia A. McDonough; Anita T. Layton. 2019. "Functional implications of the sex differences in transporter abundance along the rat nephron: modeling and analysis." American Journal of Physiology-Renal Physiology 317, no. 6: F1462-F1474.
The mechanism by which solutes accumulate in the inner medulla of the mammalian kidney has remained incompletely understood. That persistent mystery has led to hypotheses based on the peristaltic contractions of the pelvic wall smooth muscles. It has been demonstrated the peristaltic contractions propel fluid down the collecting duct in boluses. In antidiuresis, boluses are sufficiently short that collecting ducts may be collapsed most of the time. In this study, we investigated the mechanism by which about half of the bolus volume is reabsorbed into the collecting duct cells despite the short contact time. To accomplish this, we developed a dynamic mathematical model of solute and water transport along a collecting duct of a rat papilla undergoing peristaltic contractions. The model predicts that, given preexisting axial concentration gradients along the loops of Henle, ∼40% of the bolus volume is reabsorbed as the bolus flows down the inner medullary collecting duct. Additionally, simulation results suggest that while the contraction-induced luminal hydrostatic pressure facilitates water extraction from the bolus, that pressure is not necessary to concentrate the bolus. Also, neither the negative interstitial pressure generated during the relaxation phase nor the concentrating effect of hyaluronic acid has a significant effect on bolus concentration. Taken together, these findings indicate that the high collecting duct apical water permeability allows a substantial amount of water to be extracted from the bolus, despite its short transit time. However, the potential role of the peristaltic waves in the urine-concentrating mechanism remains to be revealed.
Anita T. Layton. Solute and water transport along an inner medullary collecting duct undergoing peristaltic contractions. American Journal of Physiology-Renal Physiology 2019, 317, F735 -F742.
AMA StyleAnita T. Layton. Solute and water transport along an inner medullary collecting duct undergoing peristaltic contractions. American Journal of Physiology-Renal Physiology. 2019; 317 (3):F735-F742.
Chicago/Turabian StyleAnita T. Layton. 2019. "Solute and water transport along an inner medullary collecting duct undergoing peristaltic contractions." American Journal of Physiology-Renal Physiology 317, no. 3: F735-F742.
Sex differences in blood pressure and the prevalence of hypertension are found in humans and animal models. Moreover, there has been a recent explosion of data concerning sex differences in nitric oxide, the renin-angiotensin-aldosterone system, inflammation, and kidney function. These data have the potential to reveal the mechanisms underlying male-female differences in blood pressure control. To elucidate the interactions among the multitude of physiological processes involved, one may apply computational models. In this review, we describe published computational models that represent key players in blood pressure regulation, and highlight sex-specific models and their findings.
Sameed Ahmed; Rui Hu; Jessica Leete; Anita T. Layton. Understanding sex differences in long-term blood pressure regulation: insights from experimental studies and computational modeling. American Journal of Physiology-Heart and Circulatory Physiology 2019, 316, H1113 -H1123.
AMA StyleSameed Ahmed, Rui Hu, Jessica Leete, Anita T. Layton. Understanding sex differences in long-term blood pressure regulation: insights from experimental studies and computational modeling. American Journal of Physiology-Heart and Circulatory Physiology. 2019; 316 (5):H1113-H1123.
Chicago/Turabian StyleSameed Ahmed; Rui Hu; Jessica Leete; Anita T. Layton. 2019. "Understanding sex differences in long-term blood pressure regulation: insights from experimental studies and computational modeling." American Journal of Physiology-Heart and Circulatory Physiology 316, no. 5: H1113-H1123.
We have developed the first computational model of solute and water transport from Bowman space to the papillary tip of the nephron of a human kidney. The nephron is represented as a tubule lined by a layer of epithelial cells, with apical and basolateral transporters that vary according to cell type. The model is formulated for steady state, and consists of a large system of coupled ordinary differential equations and algebraic equations. Model solution describes luminal fluid flow, hydrostatic pressure, luminal fluid solute concentrations, cytosolic solute concentrations, epithelial membrane potential, and transcellular and paracellular fluxes. We found that if we assume that the transporter density and permeabilities are taken to be the same between the human and rat nephrons (with the exception of a glucose transporter along the proximal tubule and the H+-pump along the collecting duct), the model yields segmental deliveries and urinary excretion of volume and key solutes that are consistent with human data. The model predicted that the human nephron exhibits glomerulotubular balance, such that proximal tubular Na+ reabsorption varies proportionally to the single-nephron glomerular filtration rate. To simulate the action of a novel diabetic treatment, we inhibited the Na+-glucose cotransporter 2 (SGLT2) along the proximal convoluted tubule. Simulation results predicted that the segment’s Na+ reabsorption decreased significantly, resulting in natriuresis and osmotic diuresis.
Anita T. Layton; Harold E. Layton. A computational model of epithelial solute and water transport along a human nephron. PLOS Computational Biology 2019, 15, e1006108 .
AMA StyleAnita T. Layton, Harold E. Layton. A computational model of epithelial solute and water transport along a human nephron. PLOS Computational Biology. 2019; 15 (2):e1006108.
Chicago/Turabian StyleAnita T. Layton; Harold E. Layton. 2019. "A computational model of epithelial solute and water transport along a human nephron." PLOS Computational Biology 15, no. 2: e1006108.
Anita T. Layton; Jennifer C. Sullivan. Recent advances in sex differences in kidney function. American Journal of Physiology-Renal Physiology 2019, 316, F328 -F331.
AMA StyleAnita T. Layton, Jennifer C. Sullivan. Recent advances in sex differences in kidney function. American Journal of Physiology-Renal Physiology. 2019; 316 (2):F328-F331.
Chicago/Turabian StyleAnita T. Layton; Jennifer C. Sullivan. 2019. "Recent advances in sex differences in kidney function." American Journal of Physiology-Renal Physiology 316, no. 2: F328-F331.
Anita T. Layton. Recent advances in renal epithelial transport. American Journal of Physiology-Renal Physiology 2019, 316, F274 -F276.
AMA StyleAnita T. Layton. Recent advances in renal epithelial transport. American Journal of Physiology-Renal Physiology. 2019; 316 (2):F274-F276.
Chicago/Turabian StyleAnita T. Layton. 2019. "Recent advances in renal epithelial transport." American Journal of Physiology-Renal Physiology 316, no. 2: F274-F276.
The myogenic response is a key autoregulatory mechanism in the mammalian kidney. Triggered by blood pressure perturbations, it is well established that the myogenic response is initiated in the renal afferent arteriole and mediated by alterations in muscle tone and vascular diameter that counterbalance hemodynamic perturbations. The entire process involves several subcellular, cellular, and vascular mechanisms whose interactions remain poorly understood. Here, we model and investigate the myogenic response of a multicellular segment of an afferent arteriole. Extending existing work, we focus on providing an accurate—but still computationally tractable—representation of the coupling among the involved levels. For individual muscle cells, we include detailed Ca2+ signaling, transmembrane transport of ions, kinetics of myosin light chain phosphorylation, and contraction mechanics. Intercellular interactions are mediated by gap junctions between muscle or endothelial cells. Additional interactions are mediated by hemodynamics. Simulations of time-independent pressure changes reveal regular vasoresponses throughout the model segment and stabilization of a physiological range of blood pressures (80–180 mmHg) in agreement with other modeling and experimental studies that assess steady autoregulation. Simulations of time-dependent perturbations reveal irregular vasoresponses and complex dynamics that may contribute to the complexity of dynamic autoregulation observed in vivo. The ability of the developed model to represent the myogenic response in a multiscale and realistic fashion, under feasible computational load, suggests that it can be incorporated as a key component into larger models of integrated renal hemodynamic regulation.
Maria-Veronica Ciocanel; Tracy L. Stepien; Ioannis Sgouralis; Anita T. Layton. A Multicellular Vascular Model of the Renal Myogenic Response. Processes 2018, 6, 89 .
AMA StyleMaria-Veronica Ciocanel, Tracy L. Stepien, Ioannis Sgouralis, Anita T. Layton. A Multicellular Vascular Model of the Renal Myogenic Response. Processes. 2018; 6 (7):89.
Chicago/Turabian StyleMaria-Veronica Ciocanel; Tracy L. Stepien; Ioannis Sgouralis; Anita T. Layton. 2018. "A Multicellular Vascular Model of the Renal Myogenic Response." Processes 6, no. 7: 89.
Diabetes induces glomerular hyperfiltration, affects kidney function, and may lead to chronic kidney diseases. A novel therapeutic treatment for diabetic patients targets the sodium–glucose cotransporter isoform 2 (SGLT2) in the kidney. SGLT2 inhibitors enhance urinary glucose, \(\hbox {Na}^+\) and fluid excretion and lower hyperglycemia in diabetes by inhibiting \(\hbox {Na}^+\) and glucose reabsorption along the proximal convoluted tubule. A goal of this study is to predict the effects of SGLT2 inhibitors in diabetic patients with and without chronic kidney diseases. To that end, we applied computational rat kidney models to assess how SGLT2 inhibition affects renal solute transport and metabolism when nephron population are normal or reduced (the latter simulates chronic kidney disease). The model predicts that SGLT2 inhibition induces glucosuria and natriuresis, with those effects enhanced in a remnant kidney. The model also predicts that the \(\hbox {Na}^+\) transport load and thus oxygen consumption of the S3 segment are increased under SGLT2 inhibition, a consequence that may increase the risk of hypoxia for that segment. To protect the vulnerable S3 segment, we explore dual SGLT2/SGLT1 inhibition and seek to determine the optimal combination that would yield sufficient urinary glucose excretion while limiting the metabolic load on the S3 segment. The model predicts that the optimal combination of SGLT2/SGLT1 inhibition lowers the oxygen requirements of key tubular segments, but decreases urine flow and \(\hbox {Na}^+\) excretion; the latter effect may limit the cardiovascular protection of the treatment.
Anita T. Layton. Optimizing SGLT inhibitor treatment for diabetes with chronic kidney diseases. Biological Cybernetics 2018, 113, 139 -148.
AMA StyleAnita T. Layton. Optimizing SGLT inhibitor treatment for diabetes with chronic kidney diseases. Biological Cybernetics. 2018; 113 (1-2):139-148.
Chicago/Turabian StyleAnita T. Layton. 2018. "Optimizing SGLT inhibitor treatment for diabetes with chronic kidney diseases." Biological Cybernetics 113, no. 1-2: 139-148.
In addition to being a leading cause of end-stage renal disease, diabetes mellitus is also associated with an elevated risk of heart failure. A new class of anti-hyperglycaemic drugs are the sodium-glucose cotransporter 2 (SGLT2) inhibitors, which attenuate postprandial increases in blood glucose by targeting its reabsorption along the early proximal tubule and enhancing urinary glucose excretion. Because the transport of glucose and Na+ in the proximal tubule is coupled, inhibition of SGLT2 also reduces proximal tubular Na+ and fluid reabsorption, and induces natriuresis and diuresis. This article is protected by copyright. All rights reserved.
Anita T. Layton; Volker Vallon. Cardiovascular benefits of SGLT2 inhibition in diabetes and chronic kidney diseases. Acta Physiologica 2018, 222, e13050 .
AMA StyleAnita T. Layton, Volker Vallon. Cardiovascular benefits of SGLT2 inhibition in diabetes and chronic kidney diseases. Acta Physiologica. 2018; 222 (4):e13050.
Chicago/Turabian StyleAnita T. Layton; Volker Vallon. 2018. "Cardiovascular benefits of SGLT2 inhibition in diabetes and chronic kidney diseases." Acta Physiologica 222, no. 4: e13050.