Genetic and pharmacological inhibition of microRNA-92a maintains podocyte cell cycle quiescence and limits crescentic glomerulonephritis

Abstract

Crescentic rapidly progressive glomerulonephritis (RPGN) represents the most aggressive form of acquired glomerular disease. While most therapeutic approaches involve potentially toxic immunosuppressive strategies, the pathophysiology remains incompletely understood. Podocytes are glomerular epithelial cells that are normally growth-arrested because of the expression of cyclin-dependent kinase (CDK) inhibitors. An exception is in RPGN where podocytes undergo a deregulation of their differentiated phenotype and proliferate. Here we demonstrate that microRNA-92a (miR-92a) is enriched in podocytes of patients and mice with RPGN. The CDK inhibitor p57Kip2 is a major target of miR-92a that constitutively safeguards podocyte cell cycle quiescence. Podocyte-specific deletion of miR-92a in mice de-repressed the expression of p57Kip2 and prevented glomerular injury in RPGN. Administration of an anti-miR-92a after disease initiation prevented albuminuria and kidney failure, indicating miR-92a inhibition as a potential therapeutic strategy for RPGN. We demonstrate that miRNA induction in epithelial cells can break glomerular tolerance to immune injury.

Redox signaling in aging kidney and opportunity for therapeutic intervention through natural products

“…Functional studies have shown that microRNA dysregulation is causal in myriad diseases, with microRNAs acting as activators or suppressors, and insight into the roles of microRNAs in disease progression has made microRNAs attractive targets of therapeutic modalities [96][97][98][99]. Here, we only highlight microRNA-21, -205 and -153 that play pivotal roles in renal disorders.…”

Could IL-17A Be a Novel Therapeutic Target in Diabetic Nephropathy?

“…The activity of specific miRNAs in the kidney may be modulated by in vivo delivery of mimics that restore miRNA levels or inhibitors that block miRNA function. Successful kidney transfection has been achieved by intraperitoneal, intravenous, or subcutaneous injection of either mimics or inhibitors [105,106]. Therefore, miRNA regulation has been proposed as a promising therapeutic target for DN [107,108].…”

Novel 3D analysis using optical tissue clearing documents the evolution of murine rapidly progressive glomerulonephritis

“…9 Crescentic nephritis, characterized by the rapid formation of extracapillary hypercellular lesions (crescents), is one of the most aggressive forms of kidney disease. 10 Current therapies are based on nonspecific immunosuppression, as immune cells are thought to mediate disease development and progression. 11 Importantly, recent evidence suggests that glomerular crescent formation involves also nonimmune cells, namely glomerular visceral epithelial cells (podocytes) 10 and parietal epithelial cells (PECs), 12 and interstitial fibrosis.…”