GYY4137 modulates plasminogen activator inhibitor‐1‐dependent extracelluar matrix turnover in diabetic kidney via RAR/RXR signaling

Abstract

IntroductionDiabetic kidney is associated with dysregulation of retinoic acid metabolism. Retinoic acid receptor (RARs) and Retinoid X receptor (RXRs) are nuclear receptors that function as transcriptional regulators of several genes involved in renal pathology; however, their role in the development of renal fibrosis in diabetes remains unknown. Further, peroxisome proliferator‐activated receptors (PPARs) and RAR is known to control RXR signaling leading to differential gene expression. A recent study has also linked RAR and RXR to increased expression of Plasminogen activator inhibitor‐1 (PAI‐1), a serine protease implicated in extracellular matrix (ECM) accumulation in diabetic nephropathy (DN). Hydrogen sulfide (H2S), a gasotransmitter with potent antioxidant and anti‐inflammatory property has been shown to mitigate adverse effects in DN; however, its role in targeting other molecular events in ECM turnover remains unexplored. The purpose of this study was to determine the role of RAR and RXR in the progression of DN and whether GYY4137, a H2S donor can mitigate ECM accumulation by modulation of PPAR/RAR controlled RXR signaling.MethodsC57BL6/‐Ins2Akita/J, (Akita) mice representing type‐I diabetes and C57BL6/J (WT) mice were treated without or with GYY4137 (0.5 mg/Kg/d, IP, × 8 weeks). In vitro studies were done in mouse glomerular endothelial cells (MGECs) and treated with GYY4137 (250uM) for 24 h.ResultsIn diabetic kidneys, the mRNA and protein expression of PPARγ was decreased and the expressions of RARs, RXRs and PAI‐1 were upregulated. Diabetic kidneys demonstrated increased matrix metalloproteinase‐9 expression and activity. Further, MMP‐13 was upregulated in diabetic mice. Immunohistochemistry showed increased collagen IV, laminin and fibronectin in the glomerular and interstitial areas. GYY4137 treatment reversed the changes above. In vitro studies demonstrated that PPARγ antagonism and RAR agonism in MGECs resulted in increased RXR signaling and PAI‐1 expression and was reversed following GYY4137 treatment. In addition, GYY4137 reduced the mRNA levels of Collagen IV, laminin and fibronectin and normalized the levels of elastin.In conclusion, our data suggests that RXR signaling plays a significant role in excessive ECM turnover and GYY4137 modulates RXR signaling to reduce PAI‐1 mediated renal fibrosis in type‐I diabetes.Support or Funding InformationDK104653, HL104103 and 15SDG25840013