Blockade of cysteine-rich protein 61 attenuates renal inflammation and fibrosis after ischemic kidney injury

Abstract

Emerging data have suggested that acute kidney injury (AKI) is often incompletely repaired and can lead to chronic kidney disease (CKD), which is characterized by tubulointerstitial inflammation and fibrosis. However, the underlying mechanisms linking AKI to CKD remain obscure. The present study aimed to investigate the role of cysteine-rich protein 61 (Cyr61) after unilateral kidney ischemia-reperfusion injury (IRI) in mice. After IRI, increased expression of Cyr61 was detected, predominately in the proximal tubular epithelium. This was confirmed by in vitro experiments, which showed that hypoxia stimulated Cyr61 expression in cultured proximal tubular epithelial cells. The proinflammatory property of Cyr61 was indicated by its ability to upregulate monocyte chemoattractant protein-1 and IL-6. Additionally, we found elevated urinary Cyr61 excretion in patients with AKI. Notably, treatment of mice with an anti-Cyr61 antibody attenuated the upregulation of kidney monocyte chemoattractant protein-1, IL-6, IL-1β, and macrophage inflammatory protein-2 and reduced the infiltration of F4/80-positive macrophages on days 7 and 14 after IRI. In addition, blockade of Cyr61 reduced the mRNA expression of collagen, transforming growth factor-β, and plasminogen activator inhibitor-I as well as the degree of collagen fibril accumulation, as evaluated by picrosirius red staining, and levels of α-smooth muscle actin proteins by day 14. Concurrently, in the treated group, peritubular microvascular density was more preserved on day 14. We conclude that Cyr61 blockade inhibits the triad of inflammation, interstitial fibrosis, and capillary rarefaction after severe ischemic AKI. The results of this study expand the knowledge of the mechanisms underlying the AKI-to-CKD transition and suggest that Cyr61 is a potential therapeutic target.

CCN1/CYR61-mediated meticulous patrolling by Ly6C low monocytes fuels vascular inflammation

“…Neither murine PBMCs nor endothelial cells released CCN1 on a short-term basis, although endothelial cell-derived CCN1 coats the surface of these cells in the steady state and 18-h treatment with TNF-α and bafilomycin A1 stimulated CCN1 release by human PBMCs (18). These results are in accordance with the chemoattractant properties of CCN1 for monocytes/macrophages in the early phase of inflammation, whereas PBMC-derived CCN1 locally immobilize recruited leukocytes in the invaded tissue after extravasation at later time points (18,19,(50)(51)(52)(53).…”

YAP/TAZ Are Essential for TGF-β2–Mediated Conjunctival Fibrosis

“…For example, CTGF (CCN2) and CYR61 (CCN1) are matricellular proteins that act as signaling molecules and have been implicated in pathogenic fibrosis. 50,51 TGF-b2-mediated induction of CTGF/CYR61 proteins were not suppressed unless both YAP and TAZ were silenced, but on the transcriptional level, silencing of YAP or TAZ alone significantly suppressed the TGF-b2-mediated induction of CTGF/CYR61 mRNA expression (the complete suppression of the expression of these genes was achieved only by the simultaneous knockdown of YAP and TAZ). This mRNA-protein discrepancy may be due to posttranscriptional or posttranslational regulation.…”

The matricellular protein CCN1 enhances TGF‐β1/SMAD3‐dependent profibrotic signaling in fibroblasts and contributes to fibrogenic responses to lung injury

“…It is possible that CCN1 may be beneficial in normal wound healing and tissue repair in contexts of resolving fibrosis but contribute to fibrosis in models of progressive fibrosis. Although the bleomycin model of lung fibrosis is known to be a slowly resolving model, we attempted to test the influence of targeting CCN1 by administering siRNA during the active fibrotic phase (d [8][9][10][11][12][13][14][15][16][17][18][19][20]. Future studies should address the effects of CCN1 in preclinical animal models of progressive fibrosis.…”

“…Additionally, exogenous CCN1 or genetic overexpression resulted in regression of established fibrosis in the liver (11,12). However, in some contexts, CCN1 appears to mediate proinflammatory and profibrotic effects, for example, following ischemic kidney injury (13) or unilateral ureteral obstruction (14). In the lung, CCN1 overexpression exacerbates lung injury and causes neutrophilic alveolitis and obstructive bronchiolitis in mice (15,16).…”