title: Endothelial sirtuin 1 inactivation enhances capillary rarefaction and fibrosis following kidney injury through Notch activation.
abstract: Peritubular capillary (PTC) rarefaction along with tissue fibrosis is a hallmark of chronic kidney disease (CKD). However, molecular mechanisms of PTC loss have been poorly understood. Previous studies have demonstrated that functional loss of endothelial sirtuin 1 (SIRT1) impairs angiogenesis during development and tissue damage. Here, we found that endothelial SIRT1 dysfunction causes activation of endothelial Notch1 signaling, which leads to PTC rarefaction and fibrosis following kidney injury. In mice lacking functional SIRT1 in the endothelium (Sirt1 mutant), kidney injury enhanced apoptosis and senescence of PTC endothelial cells with impaired endothelial proliferation and expanded myofibroblast population and collagen deposition. Compared to wild-type kidneys, Sirt1 mutant kidneys up-regulated expression of Delta-like 4 (DLL4, a potent Notch1 ligand), Hey1 and Hes1 (Notch target genes), and Notch intracellular domain-1 (NICD1, active form of Notch1) in microvascular endothelial cells (MVECs) post-injury. Sirt1 mutant primary kidney MVECs reduced motility and vascular assembly and enhanced senescence compared to wild-type kidney MVECs. This difference in the phenotype was negated with Notch inhibition. Concurrent stimulation of DLL4 and transforming growth factor (TGF)-β1 increased trans-differentiation of primary kidney pericytes into myofibroblast more than TGF-β1 treatment alone. Collectively, these results indicate that endothelial SIRT1 counteracts PTC rarefaction by repression of Notch1 signaling and antagonizes fibrosis via suppression of endothelial DLL4 expression.
authors.affiliation: Renal Research Institute, Department of Medicine, New York Medical College, Valhalla, NY, USA. Electronic address: yujirokida@gmail.com.
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Kida
authors.affiliation: Renal Research Institute, Department of Medicine, New York Medical College, Valhalla, NY, USA; Renal Research Institute, Department of Physiology, New York Medical College, Valhalla, NY, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Zullo
authors.affiliation: Renal Research Institute, Department of Medicine, New York Medical College, Valhalla, NY, USA; Renal Research Institute, Department of Pharmacology, New York Medical College, Valhalla, NY, USA; Renal Research Institute, Department of Physiology, New York Medical College, Valhalla, NY, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Goligorsky
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D002196:Capillaries / Q000473:pathology*; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007668:Kidney / Q000293:injuries* / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D018919:Neovascularization, Physiologic; D020286:Pericytes / Q000378:metabolism / Q000473:pathology; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000378:metabolism / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D056564:Sirtuin 1
keywords: Endothelial cell; Kidney; Notch1; Sirtuin 1