Abstract
Podocyte injury is a major determinant of proteinuric kidney disease and the identification of potential therapeutic targets for preventing podocyte injury has clinical importance. Here, we show that histone deacetylase Sirt6 protects against podocyte injury through epigenetic regulation of Notch signaling. Sirt6 is downregulated in renal biopsies from patients with podocytopathies and its expression correlates with glomerular filtration rate. Podocyte-specific deletion of Sirt6 exacerbates podocyte injury and proteinuria in two independent mouse models, diabetic nephropathy, and adriamycin-induced nephropathy. Sirt6 has pleiotropic protective actions in podocytes, including anti-inflammatory and anti-apoptotic effects, is involved in actin cytoskeleton maintenance and promotes autophagy. Sirt6 also reduces urokinase plasminogen activator receptor expression, which is a key factor for podocyte foot process effacement and proteinuria. Mechanistically, Sirt6 inhibits Notch1 and Notch4 transcription by deacetylating histone H3K9. We propose Sirt6 as a potential therapeutic target for the treatment of proteinuric kidney disease.
Highlights
Podocyte injury is a major determinant of proteinuric kidney disease and the identification of potential therapeutic targets for preventing podocyte injury has clinical importance
Our results showed that the levels of Sirt[1], Sirt[3], Sirt[4], and Sirt[6] were reduced in the kidney from STZ-induced diabetic mice
Sirt[6] was originally identified as a nuclear-localizing protein[15] and our studies showed that Sirt[6] localized in the nucleus of human podocytes, Sirt[6] was found more or less in the cytoplasm of some other renal cells by our current antibody-based molecular assays, leading us to speculate that renal Sirt[6] may shuttle between the nucleus and cytoplasm, depending on cell type or environmental stimuli
Summary
Podocyte injury is a major determinant of proteinuric kidney disease and the identification of potential therapeutic targets for preventing podocyte injury has clinical importance. Terminally differentiated epithelial cells that are integral components of the renal glomerular filtration barrier, which are vulnerable to a variety of injuries and as a result, they undergo a series of changes ranging from hypertrophy, detachment, autophagy to apoptosis[1]. (FSGS), membranous glomerulonephritis (MGN), diabetic nephropathy (DN) and IgA nephropathy In these conditions, podocytes lose specific markers of differentiation, undergo foot process effacement and eventual detachment, and reduce the capacity to maintain the glomerular filtration barrier, thereby resulting in proteinuria[3]. Identifying the key and universal molecules involved in the different forms of podocytopathies may provide clues to develop new therapeutic strategies for patients with proteinuric kidney disease. The role of Sirt[6] in the kidney keeps unclear
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