Cysteine-Rich Protein 61 Plays a Proinflammatory Role in Obstructive Kidney Fibrosis

Abstract

Cysteine-rich protein 61 (Cyr61) is a secreted matrix-associated protein that regulates a broad spectrum of biological and cellular activities. This study aimed to investigate the role of Cyr61 in progressive kidney fibrosis induced by unilateral ureteral obstruction (UUO) surgery in mice. The expression of Cyr61 transcripts and proteins in the obstructed kidneys were increased from day 1 and remained high until day 10 after surgery. Immunohistochemistry indicated that Cyr61 was expressed mainly in renal tubular epithelial cells. The upregulated Cyr61 in UUO kidneys was reduced in mice treated with pan-transforming growth factor-β (TGF-β) antibody. The role of TGF-β in tubular Cyr61 upregulation after obstructive kidney injury was further supported by experiments showing that TGF-β1 stimulated Cyr61 expression in cultured tubular epithelial cells. Notably, the upregulation of Cyr61 in UUO kidneys was followed by a marked increase in monocyte chemoattractant protein 1 (MCP-1) transcripts and macrophage infiltration, which were attenuated in mice treated with anti-Cyr61 antibodies. This proinflammatory property of Cyr61 in inducing MCP-1 expression was further confirmed in tubular epithelial cells cultured with Cyr61 protein. The anti-Cyr61 antibody in UUO mice also reduced the levels of collagen type 1-α1 transcripts, collagen fibril accumulation evaluated by picrosirius red staining, and the levels of α-smooth muscle actin (α-SMA) transcripts and proteins on day 4 after surgery; however, the antifibrotic effect was not sustained. In conclusion, the TGF-β-mediated increase in tubular Cyr61 expression involved renal inflammatory cell infiltration through MCP-1 induction during obstructive kidney injury. The Cyr61 blockade attenuated kidney fibrosis in the early phase, but the antifibrotic effect could not be sustained.

Postoperative Accumulation of Cyr61/CCN1 in Surgical Wound Fluid Precedes Cytokine Activation and is Disparate from Systemic Alterations

“…The pro-inflammatory role of CCN1 has been confirmed in independent experimental studies, demonstrating its ability to induce cytokine secretion [21,32] and to affect chemotaxis [19,20,36]. As an immediate-early gene, CCN1 is activated within minutes of cellular stimulation without requiring de novo protein synthesis [38], which may suggest that it is able to act as an upstream mediator of cytokine activation.…”

“…Attempting to identify the potential mechanisms behind these regulations, we demonstrated that CCN1 expression in parenchymal cells is sensitive to cytokine exposure in vitro. However, accumulating evidence now suggests that CCN1 may also possess pro-inflammatory capabilities [19][20][21], indicating that this immediate early gene may be involved in the initial promotion of the inflammatory response. The present study was undertaken to investigate whether CCN1 is activated at local sites of acute tissue injury in humans and to assess its temporal relationship with the activation of the inflammatory response.…”

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).…”

Gene Expression Analysis Reveals Inhibition of Radiation-Induced TGFβ-Signaling by Hyperbaric Oxygen Therapy in Mouse Salivary Glands

“…Increased Egr1 and Egr2 expression have been postulated as key mediators of TGFβ signaling and fibrosis and thereby as potential targets for antifibrotic therapy (47)(48)(49)(50). Cyr61, which is a member of the CTGF family, can be regulated by TGFβ and has proinflammatory properties (51,52). THBS1 is an activator of latent TGFβ so it can bind to its receptor (53).…”