NYMC Faculty Publications

Endothelial Sirtuin 1 Deficiency Perpetrates Nephrosclerosis Through Downregulation of Matrix Metalloproteinase-14: Relevance to Fibrosis of Vascular Senescence

Author Type(s)

Faculty

DOI

10.1681/ASN.2013010069

Journal Title

Journal of the American Society of Nephrology

First Page

276

Last Page

291

Document Type

Article

Publication Date

2-1-2014

Department

Pharmacology

Keywords

Acute Kidney Injury, Animals, Cellular Senescence, Concanavalin A, Down-Regulation, Endothelium, Vascular, Exons, Extracellular Matrix, Fibrosis, Folic Acid, Gene Expression Regulation, Enzymologic, Human Umbilical Vein Endothelial Cells, Kidney, Kidney Failure, Chronic, Male, Matrix Metalloproteinase 14, Mice, Mice, Mutant Strains, Mice, Transgenic, Neovascularization, Physiologic, Nephrosclerosis, Regeneration, Sirtuin 1, Vasodilation

Disciplines

Medicine and Health Sciences

Abstract

Sirtuin 1 (SIRT1) depletion in vascular endothelial cells mediates endothelial dysfunction and premature senescence in diverse cardiovascular and renal diseases. However, the molecular mechanisms underlying these pathologic effects remain unclear. Here, we examined the phenotype of a mouse model of vascular senescence created by genetically ablating exon 4 of Sirt1 in endothelial cells (Sirt1(endo-/-)). Under basal conditions, Sirt1(endo-/-) mice showed impaired endothelium-dependent vasorelaxation and angiogenesis, and fibrosis occurred spontaneously at low levels at an early age. In contrast, induction of nephrotoxic stress (acute and chronic folic acid-induced nephropathy) in Sirt1(endo-/-) mice resulted in robust acute renal functional deterioration followed by an exaggerated fibrotic response compared with control animals. Additional studies identified matrix metalloproteinase-14 (MMP-14) as a target of SIRT1. In the kidneys of Sirt1(endo-/-) mice, impaired angiogenesis, reduced matrilytic activity, and retention of the profibrotic cleavage substrates tissue transglutaminase and endoglin accompanied MMP-14 suppression. Furthermore, restoration of MMP-14 expression in SIRT1-depeleted mice improved angiogenic and matrilytic functions of the endothelium, prevented renal dysfunction, and attenuated nephrosclerosis. Our findings establish a novel mechanistic molecular link between endothelial SIRT1 depletion, downregulation of MMP-14, and the development of nephrosclerosis.

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