BACKGROUND AND AIMS Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, are primarily cholesterol-lowering drugs that have become standard of care in the primary and secondary prevention of cardiovascular diseases. Apart from lipid-lowering, statins may act beneficially through anti-fibrotic mechanisms to protect the diseased kidney. This study evaluated anti-fibrotic effects of rosuvastatin (RSV) in a chronic kidney fibrosis model and against the TGF-ß1 stimulated Madin-Darby canine kidney (MDCK) cells in vitro. METHOD Mice subjected to unilateral ischemic reperfusion injury with contralateral nephrectomy (uIRIx) were treated with vehicle or RSV (10 mg/kg, by oral gavage) daily for 4 weeks and kidneys were analyzed for markers of fibrosis, bone morphogenetic protein-7 (BMP-7), uterine sensitization-associated gene-1 (USAG-1), and SMAD signaling. Control and homeobox protein Hox-A13 (HOXA13) knocked down MDCK cells were stimulated with TGF- ß1 (5 ng/ml) and then treated with RSV. RESULTS Kidneys from uIRIx mice showed increased expression of α-SMA, Collagen 1 and decrease in BMP-7 (20.35 ± 2.37 versus 1.00 ± 0.27, P < 0.05; 8.43 ± 1.55 versus 1.00 ± 0.35, P < 0.05; 0.75 ± 0.06 versus 1.00 ± 0.15, P < 0.05, respectively). In contrast, expression of USAG-1, a BMP-7 antagonist, was markedly increased in fibrotic kidney (6.60 ± 1.11 versus 1.00 ± 0.02, P < 0.05). Interestingly, RSV treatment not only attenuated expression of USAG-1 (0.72 ± 0.08 versus 1.36 ± 0.14, P < 0.05) but also showed a tendency to activate expression of HOXA13 (0.36 ± 0.14 versus 0.51 ± 0.15, P > 0.05) and improved other markers of fibrosis. Moreover, RSV treatment significantly reduced phosphorylated Smad3 (3.94 ± 0.81 versus 7.17 ± 1.50, P < 0.05) and increased phosphorylation levels of Smad 1/5/9 (0.67 ± 0.10 versus 0.30 ± 0.09, P < 0.05) that is associated with BMP-7 signaling in the fibrotic kidney. MDCK cells stimulated with TGF-β1 in vitro showed increased expression of α-SMA, fibronectin, vimentin, collagen 1, USAG-1, and phosphorylation of Smad3 as well as decreased expression of phosphorylated Smad 1/5/9. RSV treatment significantly reversed these changes as well as increased level of transcriptional factor HOXA13 (0.89 ± 0.12 versus 0.33 ± 0.08, P < 0.05), which negatively regulates USAG-1, without changes in BMP-7 expression. In addition, effect of RSV treatment on USAG-1 expression was significantly decreased in HOXA13 gene knocked down MDCK cells (1.01 ± 0.19 versus 2.04 ± 0.38, P < 0.05; 1.66 ± 0.13 versus 2.04 ± 0.38, P > 0.05; TGF- ß1 + RSV versus TGF- ß1 and TGF- ß1 + RSV + siRNA vs TGF- ß1, respectively). These in vitro data suggest that RSV enhanced anti-fibrotic pathway by downregulating a dominant BMP-7 antagonist USAG-1 via HOXA13 upregulation and not by enhancing BMP-7 production. CONCLUSION The present results demonstrate that RSV inhibits the progression of kidney fibrosis in part by upregulating BMP-7-mediated signaling via HOXA13 expression and down regulation of USAG-1.
Background and Aims Frailty is a known risk factor for chronic disease and mortality. However, the association between frailty assessed by hand grip strength (HGS) and chronic kidney disease (CKD) among adults has not been elucidated. This study evaluated the association between muscle strength and the risk of CKD. Method Data were retrieved from a nationwide cohort study (Korean National Health and Nutrition Examination Surveys VI-VII, 2014-2017) and participants aged 40 to 80 years were included in the study analysis (male=6,660, female=8,195). HGS was measured using digital hand dynamometer and normalized to body mass index (BMI). The association between the risk of CKD (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 or the presence of proteinuria) and quartile of HGS per BMI was evaluated among male and female subjects. Results The mean age was 58.8 ± 11.6 years and mean eGFR level was 88.2 ± 18.7 mL/min/1.73 m2. The mean levels of HGS per BMI were 1.5 ± 0.3 and 0.9 ± 0.2 in male and female subjects, respectively. Those in higher quartile of HGS per BMI showed lower prevalences of advanced CKD stages than lowest quartile among both male and female subjects. When univariable logistic regression analysis for the risk of CKD was performed, higher quartile of HGS per BMI was significantly associated with lower risk of CKD in both male and female subjects. After adjustment for confounding factors including age, systolic blood pressure, smoking and alcohol intake, education and income levels, history of hypertension, diabetes, or arthritis, physical activity, baseline eGFR, total cholesterol, hemoglobin, and daily protein intake, the higher quartile of HGS per BMI were associated with lower risk of CKD in both male and female subjects (odds ratio [OR], 0.66; 95% confidence interval [CI], 0.49-0.88 in Q4; OR, 0.64; 95% CI 0.49-0.83 in Q3 in male; OR, 0.59; 95% CI, 0.43-0.81 in Q4; OR, 0.61; 95% CI, 0.47-0.80 in Q3; OR, 0.70;95% CI, 0.55-0.90 in Q2 in female, Q1 as reference group). These associations were consistent when the HGS per BMI was treated as continuous variable that 34% and 54% of risk was reduced as 1 m2 increase in male and female subjects. Conclusion Greater muscle strength normalized to BMI is associated with lower risk of CKD in adults. These findings suggest that frailty in adults is an important risk factor for CKD development.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.