Journal
BIOMOLECULES
Volume 11, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/biom11101477
Keywords
GYY4137; plasminogen activator inhibitor-1; retinoid X receptor; retinoic acid receptor; extracellular matrix; diabetic kidney; mesangial cells
Categories
Funding
- National Institutes of Health [DK104653, DK116591]
Ask authors/readers for more resources
The study found that in diabetic kidney, PPAR gamma expression was decreased, while RXR alpha, RXR beta, and RAR gamma 1 expression was increased, along with upregulations of PAI-1, MMP-9, and MMP-13. Additionally, collagen IV, fibronectin, and laminin expression were increased, while elastin expression was decreased in the diabetic kidney.
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 gamma (PPAR gamma) 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-Ins2(Akita)/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 PPAR gamma was decreased, whereas upregulations of RXR alpha, RXR beta, and RAR gamma 1 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available