Podocyte-specific deletion of miR-146a increases podocyte injury and diabetic kidney disease

Abstract

Diabetic glomerular injury is a major complication of diabetes mellitus and is the leading cause of end stage renal disease (ESRD). Healthy podocytes are essential for glomerular function and health. Injury or loss of these cells results in increased proteinuria and kidney dysfunction and is a common finding in various glomerulopathies. Thus, mechanistic understanding of pathways that protect podocytes from damage are essential for development of future therapeutics. MicroRNA-146a (miR-146a) is a negative regulator of inflammation and is highly expressed in myeloid cells and podocytes. We previously reported that miR-146a levels are significantly reduced in the glomeruli of patients with diabetic nephropathy (DN). Here we report generation of mice with selective deletion of miR-146a in podocytes and use of these mice in models of glomerular injury. Induction of glomerular injury in C57BL/6 wildtype mice (WT) and podocyte-specific miR-146a knockout (Pod-miR146a–/–) animals via administration of low-dose lipopolysaccharide (LPS) or nephrotoxic serum (NTS) resulted in increased proteinuria in the knockout mice, suggesting that podocyte-expressed miR-146a protects these cells, and thus glomeruli, from damage. Furthermore, induction of hyperglycemia using streptozotocin (STZ) also resulted in an accelerated development of glomerulopathy and a rapid increase in proteinuria in the knockout animals, as compared to the WT animals, further confirming the protective role of podocyte-expressed miR-146a. We also confirmed that the direct miR-146a target, ErbB4, was significantly upregulated in the diseased glomeruli and erlotinib, an ErbB4 and EGFR inhibitor, reducedits upregulation and the proteinuria in treated animals. Primary miR146–/– podocytes from these animals also showed a basally upregulated TGFβ-Smad3 signaling in vitro. Taken together, this study shows that podocyte-specific miR-146a is imperative for protecting podocytes from glomerular damage, via modulation of ErbB4/EGFR, TGFβ, and linked downstream signaling.

Exploration of the single-cell transcriptomic landscape identifies aberrant glomerular cell crosstalk in a murine model of WT1 kidney disease

“…Interactions enriched in Wt1 +/+ glomeruli included TGF-β signalling through integrin β8 ( Tgfb1-Itgb8 ), required for the release of the mature TGF-β peptide 55 and Nectin2-Nectin4 , involved in the trans-cell endocytosis of cytoplasmic cargo 56 , although neither has been investigated in the glomerulus. In Wt1 R394W/+ glomeruli, Adam17-Erbb4 was enriched, which is involved in the regulation of EGF signalling and recently implicated in glomerular injury in murine models of diabetic nephropathy 57 .…”

Pediatric Diabetic Nephropathy: Novel Insights from microRNAs

“…Worthy of note, additional miRNAs pathogenically linked to DN have been suggested as novel promising early biomarkers. Evidence on animal models and adult subjects with T2D demonstrated an inverse correlation of miRNA 146a expression with glomerular damage, suggesting a potential protective role for podocytic miR-146a in DN development [ 79 , 80 ]. Similarly, circulating miRNA-130b levels were found to be reduced in patients with a more pronounced decrease in the subgroup with microalbuminuria [ 81 ], Besides, upregulation of miRNA-424 expression was found to reduce pathological renal changes (e.g., cellular apoptosis) occurring in DN [ 82 ].…”

Broadening horizons: the contribution of mitochondria-associated endoplasmic reticulum membrane (MAM) dysfunction in diabetic kidney disease

“…In this study, Wang et al found that MAMs are rich in inflammatory response miRNAs in human and rat brains, including miR-146a, miR-142-3p and miR-142-5p 120 . Coincidentally, miR-146, miR-142-3p, and miR-142-5p have been shown to play a regulatory role in the progression of DKD inflammation 121 - 123 . Therefore, there is a possibility that MAMs participate in the inflammatory response of DKD through miRNAs.…”