miR-135 family members mediate podocyte injury through the activation of Wnt/β-catenin signaling

Abstract

The upregulation of Wnt/β-catenin signaling occurs in virtually all types of kidney disease and is associated with podocyte injury. However, the precise mechanisms involved in the development of kidney disease remain to be elucidated. MicroRNAs (miRNAs or miRs) are a class of short non-coding RNAs and they have been shown to be regulators of gene expression, mainly by binding to the untranslated region (UTR) of mRNAs. The aim of the present study was to determine the role of the 2 members of the miR-135 family (miR-135a and miR-135b) in podocyte injury and to elucidate the mechanisms responsible for the damage to podocytes. The results revealed that miR-135a and miR-135b were upregulated in models of podocyte injury and in glomeruli isolated from patients with focal segmental glomerulosclerosis (FSGS). The ectopic expression of miR-135a and miR-135b led to severe podocyte injury and the disorder of the podocyte cytoskeleton. Our findings demonstrated that miR-135a and miR-135b activated Wnt/β-catenin signaling and induced the nuclear translocation of β-catenin. Using luciferase reporter assays, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis, glycogen synthase kinase 3β (GSK3β) was identified as a target gene of miR-135a and miR-135b. To the best of our knowledge, this is the first study to demonstrate that members of the miR-135 family (specifically miR-135a and miR-135b) regulate the expression of GSK3β, thus playing a role in the development of podocyte injury and the disorder of the podocyte cytoskeleton. This is an important finding as it may contribute to the development of novel therapeutics for podocyte injury-associated glomerulopathies.

miR-135b Stimulates Osteosarcoma Recurrence and Lung Metastasis via Notch and Wnt/β-Catenin Signaling

“…Aberrantly regulated expression of miR-135b has been detected in several types of tumors including OS 25, 26. Interestingly, although not in tumors, upregulated miR-135b results in the activation of Wnt/β-catenin signaling in glomerulopathies 27 . In addition, according to a report, activated Wnt/β-catenin signaling is sufficient to activate the Notch pathway in osteocytes 28 .…”

Primary focal segmental glomerulosclerosis: miRNAs and targeted therapies

“…The miR-192 accelerates collagen formation in glomerular mesangial cells in models of diabetic nephropathy [16], and it also promotes TGF-b/Smad3-induced tubulointerstitial fibrosis [17]. These studies indicate that miRNAs play important roles in the development of glomerular diseases, particularly podocyteassociated disorders [8].…”

“…Micro-RNAs are key trans-acting factors that posttranscriptionally regulate the metazoan gene expression. In the mammalian genome, more than a thousand different miRNAs have been identified with each of them able to target hundreds of genes [3,4], some of them also involved in cellular and molecular processes of renal cells [5][6][7][8][9].…”

Interaction between miRNAs and signaling cascades of Wnt pathway in chronic lymphocytic leukemia

“…94,95 Both miR-135a and miR-135b have the ability to upregulate the Wnt signaling pathway by inhibiting GSK3β and inducing nuclear translocation of stabilized β-catenin protein. 42,96 As evident, inhibition of GSK3β results in stabilization and accumulation of β-catenin and its binding to the TCF/LEF family leads to CLL cell activation to promote blood cancer.…”