Genetic and Pharmacological Inhibition of MicroRNA-92a Maintains Podocyte Cell Cycle Quiescence and Limits Crescentic Glomerulonephritis

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

Mechanisms and consequences of TGF-ß overexpression by podocytes in progressive podocyte disease

In patients with progressive podocyte disease, such as focal segmental glomerulosclerosis (FSGS) and membranous nephropathy, upregulation of transforming growth factor-ß (TGF-ß) is observed in podocytes. Mechanical pressure or biomechanical strain in podocytopathies may cause overexpression of TGF-ß and angiotensin II (Ang II). Oxidative stress induced by Ang II may activate the latent TGF-ß, which then activates Smads and Ras/extracellular signal-regulated kinase (ERK) signaling pathways in podocytes. Enhanced TGF-ß activity in podocytes may lead to thickening of the glomerular basement membrane (GBM) by overproduction of GBM proteins and impaired GBM degradation in podocyte disease. It may also lead to podocyte apoptosis and detachment from the GBM, and epithelial-mesenchymal transition (EMT) of podocytes, initiating the development of glomerulosclerosis. Furthermore, activated TGF-ß/Smad signaling by podocytes may induce connective tissue growth factor and vascular endothelial growth factor overexpression, which could act as a paracrine effector mechanism on mesangial cells to stimulate mesangial matrix synthesis. In proliferative podocytopathies, such as cellular or collapsing FSGS, TGF-ß-induced ERK activation may play a role in podocyte proliferation, possibly via TGF-ß-induced EMT of podocytes. Collectively, these data bring new mechanistic insights into our understanding of the TGF-ß overexpression by podocytes in progressive podocyte disease

The tetraspanin CD9 controls migration and proliferation of parietal epithelial cells and glomerular disease progression

International audienc

Glomerular matrix proteins in nodular glomerulosclerosis in association with light chain deposition disease and diabetes mellitus.

The diagnosis of light chain deposition nephropathy is based on the immunohistochemical demonstration of monoclonal light chain deposits within connective tissue matrix and on the presence at the ultrastructural level of electron-dense granular deposits along glomerular and tubular basement membranes. A nodular glomerulopathy characterized by amorphous periodic acid-Schiff-positive and argyrophilic widened mesangium and nodules is described in three patients with light chain deposition nephropathy. Light microscopic examination did not allow discrimination between the glomerular changes found in these specimens and the nodular glomerulosclerosis described in four patients with well-documented diabetes mellitus. Electron microscopic examination revealed microtubular fibrils 10 to 12 nm thick in mesangial areas in both groups. Such microfibrils could be glycoproteins. Immunofluorescence localization of matrix proteins, by staining with affinity-purified antibodies to types I, III, IV, and V (A, B) collagens, fibronectin, laminin, and heparan sulfate-containing proteoglycans, showed similar distributions in the two conditions. The mechanism of this abnormal accumulation of mesangial and glomerular basement membrane matrix proteins in two different conditions remains unknown

Changes in the renal and maternal utero-placental arteries in pregnancies complicated by hypertension

peer reviewe