Clusterin Attenuates the Development of Renal Fibrosis

Abstract

Upregulation of clusterin occurs in several renal diseases and models of nephrotoxicity, but whether this promotes injury or is a protective reaction to injury is unknown. Here, in the mouse unilateral ureteral obstruction model, obstruction markedly increased the expression of clusterin, plasminogen activator inhibitor-1 (PAI-1), type I collagen, and fibronectin. Compared with wild-type mice, clusterin-deficient mice exhibited higher levels of PAI-1, type I collagen, and fibronectin and accelerated renal fibrosis in response to obstruction. In cultured rat tubular epithelium-like cells, adenovirus-mediated overexpression of clusterin inhibited the expression of TGF-b-stimulated PAI-1, type I collagen, and fibronectin. Clusterin inhibited TGF-b-stimulated Smad3 activity via inhibition of Smad3 phosphorylation and its nuclear translocation. Moreover, intrarenal delivery of adenovirus-expressing clusterin upregulated expression of clusterin in tubular epithelium-like cells and attenuated obstruction-induced renal fibrosis. In conclusion, clusterin attenuates renal fibrosis in obstructive nephropathy. These results suggest that upregulation of clusterin during renal injury is a protective response against the development of renal fibrosis.

Diagnosis and Prediction of CKD Progression by Assessment of Urinary Peptides

“…Of those, clusterin has been shown in an accelerated fibrosis model to protect against excessive fibrotic lesions. 37 Cornulin is involved in cell cycle arrest at the G1/S checkpoint by upregulating the expression of p21(WAF/CIP). 38 Progression of renal failure in a subtotal nephrectomy model in p21 knockout mice was slower and associated with a 5-fold increase in epithelial surface compared with wild-type mice, suggesting that epithelial repair is hampered in the wild-type strain.…”

Identification of the Thiol Isomerase-binding Peptide, Mastoparan, as a Novel Inhibitor of Shear-induced Transforming Growth Factor β1 (TGF-β1) Activation

“…It is of note, therefore, that clusterin can promote epithelial-to-mesenchymal transition mediated by TGF-␤1, and clusterin gene expression is highly up-regulated in response to TGF-␤1 signaling (46). In fact, clusterin has been demonstrated to attenuate renal fibrosis through TGF-␤1-dependent mechanisms (47). MMRN1 (multimerin-1) is a large, disulfide-linked protein produced by megakaryocytes and endothelial cells and found in the ␣-granules of platelets (48).…”

KS370G, a caffeamide derivative, attenuates unilateral ureteral obstruction-induced renal fibrosis by the reduction of inflammation and oxidative stress in mice

“…Renal fibrosis, characterized by tubular atrophy, interstitial inflammation and excessive accumulation of extracellular matrix (ECM) proteins, is the hallmark of the final manifestations of CKD (Jung et al, 2012). Chronic unilateral ureteral obstruction (UUO) is a representative animal model used to investigate the pathophysiology of renal fibrosis (Wu et al, 2006).…”