MicroRNA-21 in Glomerular Injury

Abstract

TGF-b 1 is a pleotropic growth factor that mediates glomerulosclerosis and podocyte apoptosis, hallmarks of glomerular diseases. The expression of microRNA-21 (miR-21) is regulated by TGF-b 1 , and miR-21 inhibits apoptosis in cancer cells. TGF-b 1 -transgenic mice exhibit accelerated podocyte loss and glomerulosclerosis. We determined that miR-21 expression increases rapidly in cultured murine podocytes after exposure to TGF-b 1 and is higher in kidneys of TGF-b 1 -transgenic mice than wild-type mice. miR-21-deficient TGF-b 1 -transgenic mice showed increased proteinuria and glomerular extracellular matrix deposition and fewer podocytes per glomerular tuft compared with miR-21 wild-type TGF-b 1 -transgenic littermates. Similarly, miR-21 expression was increased in streptozotocin-induced diabetic mice, and loss of miR-21 in these mice was associated with increased albuminuria, podocyte depletion, and mesangial expansion. In cultured podocytes, inhibition of miR-21 was accompanied by increases in the rate of cell death, TGF-b/Smad3-signaling activity, and expression of known proapoptotic miR-21 target genes p53, Pdcd4, Smad7, Tgfbr2, and Timp3. In American-Indian patients with diabetic nephropathy (n=48), albumin-to-creatinine ratio was positively associated with miR-21 expression in glomerular fractions (r=0.6; P,0.001) but not tubulointerstitial fractions (P=0.80). These findings suggest that miR-21 ameliorates TGF-b1 and hyperglycemia-induced glomerular injury through repression of proapoptotic signals, thereby inhibiting podocyte loss. This finding is in contrast to observations in murine models of tubulointerstitial kidney injury but consistent with findings in cancer models. The aggravation of glomerular disease in miR-21-deficient mice and the positive association with albumin-to-creatinine ratio in patients with diabetic nephropathy support miR-21 as a feedback inhibitor of TGF-b signaling and functions.

Absence of miR-146a in Podocytes Increases Risk of Diabetic Glomerulopathy via Up-regulation of ErbB4 and Notch-1

“…Unlike other miRNAs, hyperglycemia down-regulates miR-93 in podocytes and in glomeruli of diabetic animals, thereby increasing VEGF-A expression (21). Podocyte expressed miR-21 is a feedback inhibitor of TGF␤ signaling and protects against diabetic glomerulopathy (22). These studies show that diabetic milieu modulates expression of many different miRNAs, and does so differentially in the many cells of the glomerulus.…”

“…miRNA Analysis by qRT-PCR-MicroRNA analysis was performed using qRT-PCR protocol as previously described (22). Briefly, total RNAs or miRNA fractions were isolated from mouse kidney tissue or from mouse podocytes using miRNeasy Mini Kit (Qiagen, Valencia, CA) according to the manufacturer provided protocol and quantified using NanoDrop (ThermoFisher).…”

“…Human Samples-Human specimens and clinical data were from recently described studies (22,33). Briefly, kidney biopsy samples were collected from Southwestern American Indians enrolled in a randomized, placebo-controlled clinical trial to test the renoprotective efficacy of Losartan in early type 2 diabetic kidney disease (ClinicalTrials.gov no.…”

Mini-review: emerging roles of microRNAs in the pathophysiology of renal diseases

“…On the other hand, miR-21 was downregulated in db/db mice, and its overexpression inhibited MC proliferation (169). More severe renal phenotypes were detected in miR-21 knockout mice crossed with TGF-␤1 transgenic mice relative to TGF-␤1 transgenic mice (77). Interestingly some miRNAs like the miR-29 family members can directly regulate ECM accumulation because these miRNAs target multiple collagens and hence a decrease in their levels can augment collagen deposition in the kidney or in renal cells treated with TGF-␤1 or HG (22,34,73,148).…”

Current Opinion in the Treatment of Diabetic Nephropathy

“…35 One study has demonstrated that miR-21 overexpression can contribute to TGF-β1-induced EMT by inhibiting target smad7, and that targeting miR-21 may be a better alternative to directly suppress TGF-β1-mediated fibrosis in diabetic nephropathy. 36 Despite there are controversial reports about the role of miR-21 and miR-192 in the diabetic nephropathy, 37,38 miRNA-based therapies still hold great promise in ameliorating diabetic nephropathy. To date, the major obstacle to the therapeutic use of miRNAs is the delivery method.…”