MicroRNA-184 is a downstream effector of albuminuria driving renal fibrosis in rats with diabetic nephropathy

Abstract

Aims/hypothesisRenal fibrosis is a common complication of diabetic nephropathy and is a major cause of end-stage renal disease. Despite the suggested link between renal fibrosis and microRNA (miRNA) dysregulation in diabetic nephropathy, the identification of the specific miRNAs involved is still incomplete. The aim of this study was to investigate miRNA profiles in the diabetic kidney and to identify potential downstream targets implicated in renal fibrosis.MethodsmiRNA expression profiling was investigated in the kidneys of 8-month-old Zucker diabetic fatty (ZDF) rats during overt nephropathy. Localisation of the most upregulated miRNA was established by in situ hybridisation. The candidate miRNA target was identified by in silico analysis and its expression documented in the diabetic kidney associated with fibrotic markers. Cultured tubule cells served to assess which of the profibrogenic stimuli acted as a trigger for the overexpressed miRNA, and to investigate underlying epigenetic mechanisms.ResultsIn ZDF rats, miR-184 showed the strongest differential upregulation compared with lean rats (18-fold). Tubular localisation of miR-184 was associated with reduced expression of lipid phosphate phosphatase 3 (LPP3) and collagen accumulation. Transfection of NRK-52E cells with miR-184 mimic reduced LPP3, promoting a profibrotic phenotype. Albumin was a major trigger of miR-184 expression. Anti-miR-184 counteracted albumin-induced LPP3 downregulation and overexpression of plasminogen activator inhibitor-1. In ZDF rats, ACE-inhibitor treatment limited albuminuria and reduced miR-184, with tubular LPP3 preservation and tubulointerstitial fibrosis amelioration. Albumin-induced miR-184 expression in tubule cells was epigenetically regulated through DNA demethylation and histone lysine acetylation and was accompanied by binding of NF-κB p65 subunit to miR-184 promoter.Conclusions/interpretationThese results suggest that miR-184 may act as a downstream effector of albuminuria through LPP3 to promote tubulointerstitial fibrosis, and offer the rationale to investigate whether targeting miR-184 in association with albuminuria-lowering drugs may be a new strategy to achieve fully anti-fibrotic effects in diabetic nephropathy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-017-4248-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Long noncoding RNA growth arrest‐specific transcript 5 alleviates renal fibrosis in diabetic nephropathy by downregulating matrix metalloproteinase 9 through recruitment of enhancer of zeste homolog 2

“…Also, TGF‐β can induce the activation of α‐SMA in fibroblast cells, which facilitates the shrinkage of fibrotic tissues, thus leading to ischemia and hypoxia of renal tissues . Besides, the activation of TGF‐β1 is indicative of the occurrence of DN, and therefore, the suppressed expression of TGF‐β1 and α‐SMA may alleviate renal fibrosis . Myofibroblast marker α‐SMA can be reduced by increased expression of GAS5‐AS1 to against renal fibrosis formation .…”

“…36 Besides, the activation of TGF-β1 is indicative of the occurrence of DN, and therefore, the suppressed expression of TGF-β1 and α-SMA may alleviate renal fibrosis. [37][38][39] Myofibroblast marker α-SMA can be reduced by increased expression of GAS5-AS1 to against renal fibrosis formation. 40 The overexpression of GAS5 after injection with pcDNA-GAS5 could attenuate the cardiac fibrosis and improve cardiac function through decreasing the expression of MMP2, α-SMA, and COL I.…”

ErHuang Formula Improves Renal Fibrosis in Diabetic Nephropathy Rats by Inhibiting CXCL6/JAK/STAT3 Signaling Pathway

“…A typical characteristic of DN is excessive deposition of extracellular matrix (ECM) proteins in the mesangium and renal tubule-interstitium of the glomerulus and basement membranes. ECM accumulation subsequently leads to the expansion of mesangial matrix and thickening of the glomerular and tubular basement membranes, eventually resulting in renal fibrosis, with high morbidity and mortality rates (Hu et al, 2015;Zanchi et al, 2017). Therefore, indentation of novel interventions to prevent the progression of DN is extremely important.…”

Diabetic Nephropathy an Obvious Complication in Long Term Type 1 Diabetes Mellitus: A Case Study

“…FGF23 inhibits 1-a hydroxylase gene with consequent decreased calcitriol synthesis. The previous study shown an inverse relationship between calcitriol and renin levels [29,30].…”