Abstract
The relationship between hydrogen sulfide (H2S), microRNAs (miRs), matrix metalloproteinases (MMPs) and poly-ADP-ribose-polymerase-1 (PARP-1) in diabetic kidney remodeling remains mostly obscured. We aimed at investigating whether alteration of miR-194-dependent MMPs and PARP-1 causes renal fibrosis in diabetes kidney, and whether H2S ameliorates fibrosis. Wild type, diabetic Akita mice as well as mouse glomerular endothelial cells (MGECs) were used as experimental models, and GYY4137 as H2S donor. In diabetic mice, plasma H2S levels were decreased while ROS and expression of its modulator (ROMO1) were increased. In addition, alteration of MMPs-9, −13 and −14 expression, PARP-1, HIF1α, and increased collagen biosynthesis as well as collagen cross-linking protein, P4HA1 and PLOD2 were observed along with diminished vascular density in diabetic kidney. These changes were ameliorated by GYY4137. Further, downregulated miRNA-194 was normalized by GYY4137 in diabetic kidney. Similar results were obtained in in vitro condition. Interestingly, miR-194 mimic also diminished ROS production, and normalized ROMO1, MMPs-9, −13 and −14, and PARP-1 along with collagen biosynthesis and cross-linking protein in HG condition. We conclude that decrease H2S diminishes miR-194, induces collagen deposition and realignment leading to fibrosis and renovascular constriction in diabetes. GYY4137 mitigates renal fibrosis in diabetes through miR-194-dependent pathway.
Highlights
The roles of H2S as a potent anti-oxidant, anti-inflammatory and cytoprotective agent in diabetes and other pathophysiological conditions are well established[3,4,5,6]
(A) The mRNA and protein expression of matrix metalloproteinases (MMPs)-9 was measured by RT-PCR and Western blotting, respectively. (B) Bar graph represents mean fold change normalized with GAPDH. (C) MMP-9 activity was measured by gelatin zymography as described in the methods. (D) Bar graph represents mean fold changes of MMP-9 activity
Values are mean ± SEM, n = 6–7/group; †p < 0.05 vs. WT and *p < 0.05 vs. Akita, compared to their respective levels of mRNA and protein expression. (E–I) Increased expression of HIF1α, P4HA1 and PLOD2 in diabetic kidney was normalized by GYY4137. (E) In the mouse kidney, gene expression of HIF1α, P4HA1 and PLOD2 was measured by RT-PCR, and (F) protein expression by Western blotting. (G,H) and (I) are the bar graphs representing mean fold change of HIF1α, P4HA1, and PLOD2 respectively normalized with GAPDH
Summary
The roles of H2S as a potent anti-oxidant, anti-inflammatory and cytoprotective agent in diabetes and other pathophysiological conditions are well established[3,4,5,6]. Of the well-known factors, which increase the risk of disease, dysregulation of genetic components contributes significantly to the onset and progression of DN Of such factors, microRNAs (miRs) are small highly conserved non-coding RNA molecules that regulate post-transcriptional regulation of gene expression. The proteinases that are involved in synthesis and degradation of ECM are known as matrix metalloproteinases (MMPs) These zinc-dependent endopeptidases regulate most ECM proteins including collagen and elastin during organogenesis, growth and normal tissue turnover[18, 19]. It was reported that hyperglycemic conditions increased ROS leading to PARP activation[21], and PARP-1 deficiency alleviated diabetic kidney disease[22], the precise molecular mechanism was unknown. The roles of HIF-1, P4HA1 and PLOD2 in diabetic renal remodeling, and whether H2S has potential to regulate collagen cross-linking are not clearly understood
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