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.

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…PDGFRβ/PDGF-BB is the main signalling pathway mediating pericyte recruitment during vessel development (Hellstrom et al, 1999). This same pathway has been reported in the recruitment of pericytes to injured tissue, where they eventually contribute to fibrosis in organs such as the lung (Hung et al, 2013) and kidney (Humphreys et al, 2010;Lin et al, 2011;Schrimpf et al, 2012). Activated pericytes have been shown to detach from local capillaries, migrate to the site of injury and differentiate into myofibroblasts (Goritz et al, 2011;Lin et al, 2011;Ren et al, 2013).…”

“…However, the recruitment of pericytes following injury and their collagen-producing capacity may be dependent on both the type of injury and the tissue under investigation (Birbrair et al, 2014a;Nakagomi et al, 2011). Activated pericytes have been shown to upregulate genes associated with migration, for example ADAMTS1 and TIMP3 (Hung et al, 2013;Schrimpf et al, 2012). Furthermore, the increased motility of these cells is coordinated by the upregulation of ADAMTS1 peptidase and downregulation of TIMP3 (Schrimpf et al, 2012).…”

“…Activated pericytes have been shown to upregulate genes associated with migration, for example ADAMTS1 and TIMP3 (Hung et al, 2013;Schrimpf et al, 2012). Furthermore, the increased motility of these cells is coordinated by the upregulation of ADAMTS1 peptidase and downregulation of TIMP3 (Schrimpf et al, 2012). A study conducted by Lin et al showed detachment of pericytes at day 1 post injury.…”

Lung Pericytes and Resident Fibroblasts

“…The 45 But, compared to the well-established general models for pericyteendothelial coordination during embryogenesis, far less is understood of how lung pericytes act on the vasculature during homeostasis, degeneration, or regeneration. 5,6,18 The receptor, PDGFR-b, marks pericytes and establishes their interactions with endothelial cells.…”

EphrinB2 Reverse Signaling Protects against Capillary Rarefaction and Fibrosis after Kidney Injury

“…Recent studies have identified a critical connection between PTC rarefaction and the development of interstitial fibrosis of the kidney. 4,5 Kidney pericytes are an extensive population of mesenchyme-derived cells that are attached to endothelial cells (ECs) of PTCs where they perform vascular stabilizing and regulatory functions. [4][5][6][7][8][9] However, in response to sustained injury, pericytes detach themselves from ECs and become scar-forming myofibroblasts, while simultaneously losing normal pericyte functions.…”