Background. Triptolide has been used for treating various autoimmune diseases. However, it remains unclear whether triptolide exerts effects on extracellular matrix (ECM) synthesis, which plays an important role in renal fibrosis. Methods. NRK-49F cells stimulated with TGF-β1 were incubated with triptolide in various concentrations. ECM proteins, including collagen type III and fibronectin, were detected using the reverse transcription real-time PCR and ELISA methods. MAPK and Smad2/3 phosphorylation were measured with western blot. P38 and ERK 1/2 pathways were inhibited with the specific inhibitors, SB203580 and PD98059. The Smad2 signal was blocked with the siRNA method. Results. Triptolide inhibited ECM synthesis in TGF-β1-stimulated NRK-49F cells in a concentration-dependent manner. Triptolide enhanced TGF-β1-induced activation of the p38, ERK 1/2 signals, whereas it inhibited Smad2 activation. There was no crosstalk between the p38, ERK 1/2 and Smad2 pathways in NRK-49F cells. Inhibition of either the p38 or ERK 1/2 signals reduced ECM synthesis. Triptolide downregulated synthesis of fibronectin and collagen type III in TGF-β1-stimulated cells treated with SB203580 and/or PD98059. SB203580 and/or PD98059 significantly repressed synthesis of fibronectin and collagen type III in TGF-β1-stimulated cells treated with triptolide. Smad2 inhibition by siRNA significantly reduced ECM synthesis. However, ECM synthesis in NRK-49F cells transfected with Smad2 siRNA and treated by triptolide was increased compared with Smad2 siRNA-transfected cells. Conclusion. The effect of triptolide to suppress ECM synthesis by inhibiting Smad2 activation may surpass its stimulating effect on ECM synthesis by activation of p38 and ERK 1/2, leading to a total inhibition of ECM synthesis in TGF-β1-stimulated NRK-49F cells.

Aims: To study the effects of simvastatin on oxidative stress in rats with early stage diabetic nephropathy. Methods: 60 male Sprague-Dawley rats were divided into three groups: control group (CN), streptozotocin (STZ)-induced diabetic rats group (DM) and STZ-induced diabetic rats group treated with simvastatin (DM+S). The following parameters were measured at weeks 6 and 12 in similar rats chosen randomly from each group: body and kidney weight, 24-hour urinary albumin excretion (UAE), biochemical indexes including blood glucose (GLU), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides (TG), serum creatinine (SCr), antioxidant enzymes including superoxide dismutase (SOD), glutathione S-transferase (GST), catalase (CAT) in plasma, lipid peroxidation production as malondialdehyde in plasma (MDAp) and erythrocytes (MDAe), morphology parameters such as glomerular volume (GV) and mesangial area/total glomerular area (M/T). Results: At weeks 6 and 12, GLU and kidney weight to body weight ratio were notably increased in both of the diabetic groups compared with those in the CN group without significant differences between the two diabetic groups. There were no significant differences of SCr, LDL, HDL and TG among all groups within all the experimental time. MDAp and MDAe were significantly increased in both of the diabetic groups, especially at week 12, while SOD, GST and CAT were significantly decreased compared with those in the CN group. At week 12, GV, M/T and UAE were also increased in the two diabetic groups. However, in the DM+S group, changes of lipid peroxidation production, antioxidant enzymes, UAE and GV were less pronounced than those in the DM group. Pearson’s correlation analysis and regression analysis shown that MDAp was increased while SOD, GST and CAT in plasma were decreased with elevation of UAE, GV and M/T. Conclusion: Increased lipid peroxidation and decreased antioxidant enzymes in plasma may play a role in the progression of diabetic nephropathy. Simvastatin may ameliorate these changes to protect kidney from oxidative lesion in diabetes even in the absence of lipid abnormalities.

Background: Mineralocorticoid receptor blockade could be a potential approach for the inhibition of chronic kidney disease (CKD) progression. The benefits and harms of different mineralocorticoid receptor antagonists (MRAs) in CKD are inconsistent. Objectives: The aim of the study was to summarize the benefits and harms of MRAs for CKD patients. Methods: We searched MEDLINE, EMBASE, and the Cochrane databases for trials assessing the effects of MRAs on non-dialysis-dependent CKD populations. Treatment and adverse effects were summarized using meta-analysis. Results: Fifty-three trials with 6 different MRAs involving 22,792 participants were included. Compared with the control group, MRAs reduced urinary albumin-to-creatinine ratio (weighted mean difference [WMD], −90.90 mg/g, 95% CI, −140.17 to −41.64 mg/g), 24-h urinary protein excretion (WMD, −0.20 g, 95% CI, −0.28 to −0.12 g), estimated glomerular filtration rate (eGFR) (WMD, −1.99 mL/min/1.73 m2, 95% CI, −3.28 to −0.70 mL/min/1.73 m2), chronic renal failure events (RR, 0.86, 95% CI, 0.79–0.93), and cardiovascular events (RR, 0.84, 95% CI, 0.77–0.92). MRAs increased the incidence of hyperkalemia (RR, 2.04, 95% CI, 1.73–2.40) and hypotension (RR, 1.80, 95% CI, 1.41–2.31). MRAs reduced the incidence of peripheral edema (RR, 0.65, 95% CI, 0.56–0.75) but not the risk of acute kidney injury (RR, 0.94, 95% CI, 0.79–1.13). Nonsteroidal MRAs (RR, 0.66, 95% CI, 0.57–0.75) but not steroidal MRAs (RR, 0.20, 95% CI, 0.02–1.68) significantly reduced the risk of peripheral edema. Steroidal MRAs (RR, 5.68, 95% CI, 1.26–25.67) but not nonsteroidal MRAs (RR, 0.52, 95% CI, 0.22–1.22) increased the risk of breast disorders. Conclusions: In the CKD patients, MRAs, particularly in combination with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, reduced albuminuria/proteinuria, eGFR, and the incidence of chronic renal failure, cardiovascular and peripheral edema events, whereas increasing the incidence of hyperkalemia and hypotension, without the augment of acute kidney injury events. Nonsteroidal MRAs were superior in the reduction of more albuminuria with fewer peripheral edema events and without the augment of breast disorder events.

Aim: To investigate the relationship between hemoglobin levels and the progression of IgA nephropathy (IgAN). Methods: In a two-center cohort of 1,828 cases with biopsy-proven IgAN, we examined the association of hemoglobin levels with the primary outcome of a composite of all-cause mortality or kidney failure defined as a 40% decline in eGFR, or ESKD (defined as eGFR <15 mL/min/1.73 m² or need for kidney replacement therapy including hemodialysis, peritoneal dialysis, or kidney transplantation), or the outcome of kidney failure, assessed using Cox and logistic regression models, respectively, with adjustment for confounders. Results: At baseline, mean age, eGFR, and hemoglobin levels were 33.75 ± 11.03 years, 99.70 ± 30.40 mL/min/1.73 m², and 123.47 ± 18.36 g/L, respectively. During a median of approximately 7-year follow-up, 183 cases reached the composite outcome. After adjustment for demographic and IgAN-specific covariates and treatments, a lower quartile of hemoglobin was nonlinearly associated with an increased risk of the primary outcome or kidney failure in the Cox proportional hazards models (primary outcome: HR for quartile 3 vs. 4, 1.37; 95% CI, 0.83–2.25; HR for quartile 2 vs. 4, 1.18; 95% CI, 0.68–2.07; HR for quartile 1 vs. 4, 1.91; 95% CI, 1.15–3.17; kidney failure: HR for quartile 3 vs. 4, 1.39; 95% CI, 0.84–2.31; HR for quartile 2 vs. 4, 1.20; 95% CI, 0.68–2.11; HR for quartile 1 vs. 4, 1.83; 95% CI, 1.09–3.07) in the fully adjusted model. Then, hemoglobin levels were transformed to a binary variable for fitting the model according to the criteria for anemia of 110 g/L in the women and 120 g/L in men in China. The participants in the anemia group had an increased risk of developing outcomes compared with the nonanemia group in both genders (primary outcome: male: HR, 1.64; 95% CI, 1.01–2.68; female: HR, 1.68; 95% CI, 1.02–2.76; kidney failure: male: HR, 1.60; 95% CI, 0.97–2.64; female: HR, 1.58; 95% CI, 0.95–2.61) in the fully adjusted model. Conclusions: A low level of hemoglobin was nonlinearly associated with IgAN progression. The anemic IgAN patients presented a higher risk of developing poor outcomes compared with the nonanemic patients.

Focal segmental glomerulosclerosis (FSGS) is the most common glomerular etiology of end-stage kidney disease (ESKD). Increasing evidence has indicated the reparative potential of mesenchymal stem cells (MSCs) in damaged diseased kidneys. However, the effect of bone marrow mesenchymal stem cells (BMSCs) on the FSGS progression remains unclear. This study aimed to investigate the protective effects of BMSCs on FSGS progression. A rat model of FSGS was generated via unilateral nephrectomy plus adriamycin injection. Rat BMSCs were isolated and characterized on the basis of their differentiative potential towards adipocytes and osteoblasts and via flow cytometry analysis. Thereafter, rat BMSCs were transplanted into FSGS recipients through the caudal vein. After 8 weeks, 24-h proteinuria, serum creatinine, and urea nitrogen levels were determined. Renal morphology was assessed using a light and transmission electron microscope. MMP9 and TIMP-1 positive cells were detected via immunohistochemical analysis. Expression levels of proinflammatory cytokines IL-6 and TNF-α were examined via RT-PCR. The isolated adherent cells from the bone marrow of rats were phenotypically and functionally equivalent to typical MSCs. Clinical examination revealed that BMSC transplantation reduced the 24-h urinary protein excretion, and serum creatinine and urea nitrogen levels. Renal morphology was ameliorated in BMSCs-transplanted rats. Mechanistically, BMSC transplantation significantly downregulated TIMP-1 and upregulated MMP9, thereby increasing the renal MMP9/TIMP-1 ratio. Moreover, BMSC transplantation also downregulated IL-6 and TNF-α. BMSC transplantation can attenuate FSGS progression in a rat model of FSGS, thereby providing a theoretical foundation for the application of autologous BMSCs in clinical FSGS therapy.

Objective: C4 deficiency is the most commonly inherited immune disorder in human. The present study investigated the characteristics of the IgAN patients with low serum C4 levels. Methods: We performed a prospective observational study. Clinical as well as histopathologic parameters were assessed. A Kaplan–Meier survival analysis was performed concerning the primary outcome defined as the serum creatinine increased 1.5-fold from baseline. The prognostic significances of clinical and histopathologic parameters were determined using Cox proportional hazards models. Results: Five-hundred twelve biopsy proven IgAN cases were available for analysis with a median follow-up of 38.4 months. Ninety-nine cases (19.34%) presented with low C4 levels (LowC4 group) and the other 413 cases did not (NlowC4 group). At the time of renal biopsy, renal injury was lighter in the LowC4 group compared with the NlowC4 group. Renal C4 deposition was significantly decreased while IgM deposition was increased in the LowC4 group. A correlation analysis shows that lower C4 levels were associated with better renal presentations at biopsy. However, the risk of developing the primary outcome was significantly greater in those with low C4 levels. Specifically, during the follow-up period, the risk of developing primary outcome was nearly ten folds higher in those with low C4, compared to those without low C4. Conclusion: There is a high prevalence of low C4 levels in IgAN patients. These patients with low C4 levels exhibited better renal presentations at the time of renal biopsy, whereas might be associated with a poor prognosis.