PP2 Ameliorates Renal Fibrosis by Regulating the NF-κB/COX-2 and PPARγ/UCP2 Pathway in Diabetic Mice.

Runmei Li,Yonghong Shi,Yang Li,Huijun Duan,Xiuyuan Li,Haijiang Wu,Liang-Jun Yan,Jinying Wei,Xinna Deng,Shan Song,Zhaohua Yang

doi:10.1155/2021/7394344

Abstract

Renal fibrosis is characterized by glomerulosclerosis and tubulointerstitial fibrosis in diabetic nephropathy (DN). We aimed to evaluate the effects of PP2 on renal fibrosis of DN. GSE33744 and GSE86300 were downloaded from the GEO database. Firstly, 839 DEGs were identified between nondiabetic and diabetic mice renal glomerular samples. COX-2 was selected to assess the effects of PP2 on renal glomerulosclerosis. In db/db mice, PP2 decreased the expression of COX-2, phosphorylated p65, and fibrotic proteins, accompanied with attenuated renal glomerulosclerosis. In cultured glomerular mesangial cells, high glucose- (HG-) induced p65 phosphorylation and COX-2 expression were attenuated by PP2 or NF-κB inhibitor PDTC. PP2, PDTC, or COX-2 inhibitor NS-398 ameliorated abnormal proliferation and expression of fibrotic proteins induced by HG. Secondly, 238 DEGs were identified between nondiabetic and diabetic mice renal cortex samples. UCP2 was selected to assess the effects of PP2 on renal tubulointerstitial fibrosis. In db/db mice, PP2 decreased the expression of PPARγ and UCP2, accompanied with attenuated renal tubulointerstitial fibrosis and EMT. In cultured proximal tubular cells, HG-induced PPARγ and UCP2 expression was inhibited by PP2 or PPARγ antagonist GW9662. PP2, GW9662, or UCP2 shRNA ameliorated HG-induced EMT. These results indicated that PP2 ameliorated renal fibrosis in diabetic mice.

Highlights

Diabetic nephropathy (DN), a major microvascular complication of diabetes mellitus, is the leading cause of end-stage renal disease
Gene Ontology (GO) functional enrichment analysis of differentially expressed genes (DEGs) was categorized based on biological processes, cellular components, and molecular functions
Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis demonstrated that the DEGs were enriched in 23 pathways (Figure 1(g))

Summary

Introduction

Diabetic nephropathy (DN), a major microvascular complication of diabetes mellitus, is the leading cause of end-stage renal disease. The pathogenesis and development of DN are extremely complicated. It is initially characterized by an increase in urinary albumin excretion, followed by a gradual decline in glomerular filtration rate, eventually progressing to end-stage renal disease [1]. It is featured by thickening glomerular basement membrane and renal tubular basement membrane, widening mesangial matrix, glomerular sclerosis, podocyte loss, tubular atrophy and increased apoptosis, renal inflammatory infiltration, and renal interstitial fibrosis. It is extremely important to understand the molecular mechanisms of DN and identify novel therapeutic targets

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