title: Pericyte TIMP3 and ADAMTS1 modulate vascular stability after kidney injury.
abstract: Kidney pericytes are progenitors of scar-forming interstitial myofibroblasts that appear after injury. The function of kidney pericytes as microvascular cells and how these cells detach from peritubular capillaries and migrate to the interstitial space, however, are poorly understood. Here, we used an unbiased approach to identify genes in kidney pericytes relevant to detachment and differentiation in response to injury in vivo, with a particular focus on genes regulating proteolytic activity and angiogenesis. Kidney pericytes rapidly activated expression of a disintegrin and metalloprotease with thrombospondin motifs-1 (ADAMTS1) and downregulated its inhibitor, tissue inhibitor of metalloproteinase 3 (TIMP3) in response to injury. Similarly to brain pericytes, kidney pericytes bound to and stabilized capillary tube networks in three-dimensional gels and inhibited metalloproteolytic activity and angiogenic signaling in endothelial cells. In contrast, myofibroblasts did not have these vascular stabilizing functions despite their derivation from kidney pericytes. Pericyte-derived TIMP3 stabilized and ADAMTS1 destabilized the capillary tubular networks. Furthermore, mice deficient in Timp3 had a spontaneous microvascular phenotype in the kidney resulting from overactivated pericytes and were more susceptible to injury-stimulated microvascular rarefaction with an exuberant fibrotic response. Taken together, these data support functions for kidney pericytes in microvascular stability, highlight central roles for regulators of extracellular proteolytic activity in capillary homoeostasis, and identify ADAMTS1 as a marker of activation of kidney pericytes.
authors.affiliation: Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schrimpf
authors.forename: Cuiyan
authors.initials: C
authors.lastname: Xin
authors.forename: Gabriella
authors.initials: G
authors.lastname: Campanholle
authors.forename: Sean E
authors.initials: SE
authors.lastname: Gill
authors.forename: William
authors.initials: W
authors.lastname: Stallcup
authors.forename: Shuei-Liong
authors.initials: SL
authors.lastname: Lin
authors.forename: George E
authors.initials: GE
authors.lastname: Davis
authors.forename: Sina A
authors.initials: SA
authors.lastname: Gharib
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Humphreys
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duffield
mesh_terms: D051722:ADAM Proteins / Q000502:physiology*; D000071097:ADAMTS1 Protein; D000818:Animals; D002196:Capillaries / Q000503:physiopathology; D002448:Cell Adhesion; D002478:Cells, Cultured; D006801:Humans; D007668:Kidney / Q000098:blood supply*; D007674:Kidney Diseases / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000502:physiology; D018919:Neovascularization, Physiologic; D020411:Oligonucleotide Array Sequence Analysis; D020286:Pericytes / Q000502:physiology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000502:physiology*; D014517:Ureteral Obstruction / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3; D042461:Vascular Endothelial Growth Factor A; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human; C486323:Adamts1 protein, mouse