title: Endothelial sirtuin 1 deficiency perpetrates nephrosclerosis through downregulation of matrix metalloproteinase-14: relevance to fibrosis of vascular senescence.
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.
authors.affiliation: Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York;
authors.forename: Radovan
authors.initials: R
authors.lastname: Vasko
authors.forename: Sandhya
authors.initials: S
authors.lastname: Xavier
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Chi Hua Sarah
authors.initials: CH
authors.lastname: Lin
authors.forename: Brian
authors.initials: B
authors.lastname: Ratliff
authors.forename: May
authors.initials: M
authors.lastname: Rabadi
authors.forename: Julien
authors.initials: J
authors.lastname: Maizel
authors.forename: Rina
authors.initials: R
authors.lastname: Tanokuchi
authors.forename: Frank
authors.initials: F
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Cao
authors.forename: Michael S
authors.initials: MS
authors.lastname: Goligorsky
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism; D000818:Animals; D016922:Cellular Senescence; D003208:Concanavalin A / Q000494:pharmacology; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000503:physiopathology; D005091:Exons / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis; D005492:Folic Acid / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D007668:Kidney / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D007676:Kidney Failure, Chronic / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D009400:Nephrosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D012038:Regeneration; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014664:Vasodilation
chemical_list: C507096:Mmp14 protein, mouse; D003208:Concanavalin A; D005492:Folic Acid; D053511:Matrix Metalloproteinase 14; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1