Variations in MicroRNA-25 Expression Influence the Severity of Diabetic Kidney Disease

Abstract

Diabetic nephropathy is characterized by persistent albuminuria, progressive decline in GFR, and secondary hypertension. MicroRNAs are dysregulated in diabetic nephropathy, but identification of the specific microRNAs involved remains incomplete. Here, we show that the peripheral blood from patients with diabetes and the kidneys of animals with type 1 or 2 diabetes have low levels of microRNA-25 (miR-25) compared with those of their nondiabetic counterparts. Furthermore, treatment with high glucose decreased the expression of miR-25 in cultured kidney cells. In / mice, systemic administration of an miR-25 agomir repressed glomerular fibrosis and reduced high BP. Notably, knockdown of miR-25 in normal mice by systemic administration of an miR-25 antagomir resulted in increased proteinuria, extracellular matrix accumulation, podocyte foot process effacement, and hypertension with renin-angiotensin system activation. However, excessive miR-25 did not cause kidney dysfunction in wild-type mice. RNA sequencing showed the alteration of miR-25 target genes in antagomir-treated mice, including the Ras-related gene CDC42. , cotransfection with the miR-25 antagomir repressed luciferase activity from a reporter construct containing the CDC42 3' untranslated region. In conclusion, these results reveal a role for miR-25 in diabetic nephropathy and indicate a potential novel therapeutic target for this disease.

Altered Expression of Long Noncoding and Messenger RNAs in Diabetic Nephropathy following Treatment with Rosiglitazone

“…GSE87899 (GEO DataSets) [33] showed increased lncRNA-AI838599 expression in the kidney of D2.B6-Ins2 Akita /MatbJ DN mouse model compared to the wild type. e similar expression trend of lncRNA-AI838599 was also seen in miR-25 knockdown mice that show similar phenotypes of DN such as proteinuria, extracellular matrix accumulation, and podocyte foot process effacement [34]. Although the lncRNA expression profile change caused by rosiglitazone administration was generally enriched in metabolic-related pathways, the TNFα signaling via NFκb gene set was regulated in the opposite direction by DN and rosiglitazone treatment, and including three lncRNA-AI838599 coexpressed mRNAs (the molecular function of lncRNA predicted by bioinformatics), Gadd45b, Per1, and Sphk1, as core enrichment.…”

MicroRNA and Microvascular Complications of Diabetes

“…miR-25 is downregulated in both human and experimental DN, and this deficiency has detrimental effects on both MCs and TECs as miR-25 prevents TEC apoptosis by modulating the phosphatase and tensin homolog (PTEN)/Akt pathway and reduces oxidative stress in MCs by targeting NADPH oxidase 4 (Nox4). Consistent with a protective role of miR-25, systemic administration of a miR-25 mimic ameliorated DN [ 66 – 68 ]. Several other miRNAs affect apoptosis; however, given their predominant effect on fibrotic processes, they will be described in the next session.…”

Upregulated microRNAs in membranous glomerulonephropathy are associated with significant downregulation of IL6 and MYC mRNAs

“…Despite the fact that an important role of miRNAs in kidney diseases has been reported (Cui et al, 2017; Y. Liu et al, 2017;Yang, Liu, et al, 2017), -107, miR-423-5p, miR-516-3p, miR-532-3p, and miR-1275) and 1 downregulated (miR-129-3p). Little is known about these miRNAs and their involvement in kidney physiology and pathology;…”