Abstract
Diabetic kidney is associated with an accumulation of extracellular matrix (ECM) leading to renal fibrosis. Dysregulation of retinoic acid metabolism involving retinoic acid receptors (RARs) and retinoid X receptors (RXRs) has been shown to play a crucial role in diabetic nephropathy (DN). Furthermore, RARs and peroxisome proliferator-activated receptor γ (PPARγ) are known to control the RXR-mediated transcriptional regulation of several target genes involved in DN. Recently, RAR and RXR have been shown to upregulate plasminogen activator inhibitor-1 (PAI-1), a major player involved in ECM accumulation and renal fibrosis during DN. Interestingly, hydrogen sulfide (H2S) has been shown to ameliorate adverse renal remodeling in DN. We investigated the role of RXR signaling in the ECM turnover in diabetic kidney, and whether H2S can mitigate ECM accumulation by modulating PPAR/RAR-mediated RXR signaling. We used wild-type (C57BL/6J), diabetic (C57BL/6-Ins2Akita/J) mice and mouse mesangial cells (MCs) as experimental models. GYY4137 was used as a H2S donor. Results showed that in diabetic kidney, the expression of PPARγ was decreased, whereas upregulations of RXRα, RXRβ, and RARγ1 expression were observed. The changes were associated with elevated PAI-1, MMP-9 and MMP-13. In addition, the expressions of collagen IV, fibronectin and laminin were increased, whereas elastin expression was decreased in the diabetic kidney. Excessive collagen deposition was observed predominantly in the peri-glomerular and glomerular regions of the diabetic kidney. Immunohistochemical localization revealed elevated expression of fibronectin and laminin in the glomeruli of the diabetic kidney. GYY4137 reversed the pathological changes. Similar results were observed in in vitro experiments. In conclusion, our data suggest that RXR signaling plays a significant role in ECM turnover, and GYY4137 modulates PPAR/RAR-mediated RXR signaling to ameliorate PAI-1-dependent adverse ECM turnover in DN.
Highlights
Diabetic kidney is associated with an accumulation of extracellular matrix (ECM) leading to renal fibrosis
Renal fibrosis is characterized by the excessive synthesis and deposition of ECM proteins leading to end-stage renal disease (ESRD) and kidney failure
Several studies have revealed that a reduction in endogenous synthesis of hydrogen sulfide (H2 S) and H2 S-producing enzymes are correlated with excessive ECM accumulation in the diabetic kidney, whereas the induction of H2 S by exogenous administration ameliorates ECM remodeling [13,77,78]
Summary
Diabetic kidney is associated with an accumulation of extracellular matrix (ECM) leading to renal fibrosis. RAR and RXR have been shown to upregulate plasminogen activator inhibitor-1 (PAI-1), a major player involved in ECM accumulation and renal fibrosis during DN. We investigated the role of RXR signaling in the ECM turnover in diabetic kidney, and whether H2 S can mitigate ECM accumulation by modulating PPAR/RAR-mediated RXR signaling. Our data suggest that RXR signaling plays a significant role in ECM turnover, and GYY4137 modulates. The pathogenesis of DN is manifested by progressive glomerular and tubulointerstitial fibrosis, which is characterized by the excessive accumulation and deposition of extracellular matrix (ECM) proteins, leading to mesangial expansion and thickening of the glomerular basement membrane [2,6]. PAI-1 inhibits plasminogen activators that convert plasminogen to plasmin which, in turn degrades a wide range of published maps and institutional affiliations
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