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MiRNA-27b-3p and miRNA-1228-3p correlate with the progression of Kidney Fibrosis in Diabetic Nephropathy

ABSTRACT: Diabetic Nephropathy (DN) is a chronic complication of diabetes and the primary cause of end stage renal disease. DN can be differentially diagnosed only through histological investigation. Therefore, there is need for molecular biomarkers, such as miRNAs, to discriminate among different histological lesions in diabetics. Aim of this study was to identify a pattern of differentially expressed miRNAs in kidney biopsies of DN patients and to assess their potential as differential diagnostic biomarkers. Using microarray, we assayed miRNA expression in kidney tissue from 8 DN patients, 6 diabetic patients with membranous nephropathy and 4 patients with normal histology. Nine miRNAs were differentially expressed among the three groups of patients, thus underlying their potential role as markers of specific histological damage. In silico we identified 2 miRNAs (i.e., miR-27b-3p and miR-1228-3p) showing an interaction with UBE2v1, an ubiquitin-conjugating E2 enzyme variant that mediates the formation of lysine 63-linked ubiquitin chains, a mechanism we showed as involved in DN kidney fibrosis. Both miRNAs were confirmed to be down-regulated in DN biopsies, using qPCR and in situ hybridization, and in urines of DN patients. Interestingly, the urinary levels of both miRNAs were also able to discriminate among different degrees of renal fibrosis. Finally, we showed that the combined urinary expression of both miRNAs was also able to discriminate DN patients from other glomerulonephritides, both in the presence and absence of T2D. We identified two regulatory miRNAs potentially useful as diagnostic biomarkers of tubular-interstitial fibrosis in diabetic patients with DN.

ORGANISM(S): Homo sapiens

PROVIDER: GSE51674 | GEO | 2019/08/21

REPOSITORIES: GEO

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Project description:Gene expression profiling of kidneys from the murine model of HIV-associated nephropathy (HIVAN) identified an association between the expression of an endoplasmic reticulum (ER)-associated protein reticulon-1, RTN1, and the severity of kidney disease. Of the three known RTN1 isoforms, only RTN1A protein expression was increased in kidneys of murine models of HIVAN, diabetic nephropathy (DN), and renal fibrosis and humans with HIVAN and DN. Both mRNA and protein expression of RTN1-A in the kidneys correlated inversely with estimated glomerular filtration rate (eGFR) in patients with DN. In kidney cells, RTN1 overexpression induced ER stress/apoptosis, whereas RTN1 knockdown attenuated tunicamycin-, and hyperglycemia-induced ER stress/apoptosis. Incubation of kidney cells with high glucose media induced RTN1A expression likely through oxidative pathway, while knockdown of RTN1A inhibited high glucose-induced apoptosis. RTN1A interacts with PERK and mutation of its N- or C-terminal domain abolished its effects on ER stress/apoptosis. In vivo, knockdown of Rtn1a expression either before or after kidney injury attenuated renal fibrosis in mice with unilateral ureteral obstruction (UUO) and tubular epithelial cell-specific knockdown of Rtn1a also ameliorated ER stress and renal fibrosis in the UUO mice. Finally, knockdown of Rtn1a also attenuated proteinuria, glomerular hypertrophy, and mesangial expansion in STZ-induced diabetic mice, which were associated with suppression of ER stress markers. Taken together, these data suggest that RTN1 is a mediator of kidney disease progression that exacerbates kidney injury through ER stress and apoptosis. Animal studies: All animal studies were approved by the IACUC committee of Mount Sinai School of Medicine. HIV-1 transgenic mice, Tg26, and their littermates were generated and genotyped as described. Only male heterozygous Tg26 in the FVB/N background were used in the study, because homozygous HIV-transgenic mice are not viable for more than few weeks postnatally. UUO and folic acid-induced nephropathy models were created as described . Mice were grouped as wild type, Tg26 with mild kidney injury, Tg26, with serious kidney injury. The kidneys were collected from these mice for histology, western blot, real-time PCR analysis, and microarray studies. Kidney disease was confirmed by measurement of proteinuria, renal function, and histologic analysis. Microarray studies: Affymetrix gene expression microarrays were performed at the Mount Sinai Institution Microarray Core Facility. The Affymetrix GeneChip® Mouse Genome 430 2.0 Array was used to profile gene expression in the kidney cortex of Tg26 and WT mice 37. One-way analysis of variance test (ANOVA) was applied to the dataset to identify the genes that were differentially expressed between the two groups. P-values were corrected using Benjamini–Hochberg false discovery rate (FDR) with a threshold of 0.05.

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MiRNA-27b-3p and miRNA-1228-3p correlate with the progression of Kidney Fibrosis in Diabetic Nephropathy

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