Angiotensin II increases fibronectin and collagen I through the β-catenin-dependent signaling in mouse collecting duct cells

Abstract

Cuevas CA, Gonzalez AA, Inestrosa NC, Vio CP, Prieto MC. Angiotensin II increases fibronectin and collagen I through the ␤-catenin-dependent signaling in mouse collecting duct cells. Am J Physiol Renal Physiol 308: F358 -F365, 2015. First published November 19, 2014 doi:10.1152/ajprenal.00429.2014.-The contribution of angiotensin II (ANG II) to renal and tubular fibrosis has been widely reported. Recent studies have shown that collecting duct cells can undergo mesenchymal transition suggesting that collecting duct cells are involved in interstitial fibrosis. The Wnt/␤-catenin signaling pathway plays an essential role in development, organogenesis, and tissue homeostasis; however, the dysregulation of this pathway has been linked to fibrosis. In this study, we investigated whether AT1 receptor activation induces the expression of fibronectin and collagen I via the ␤-catenin pathway in mouse collecting duct cell line M-1. ANG II (10 Ϫ7 M) treatment in M-1 cells increased mRNA, protein levels of fibronectin and collagen I, the ␤-catenin target genes (cyclin D1 and c-myc), and the myofibroblast phenotype. These effects were prevented by candesartan, an AT 1 receptor blocker. Inhibition of the ␤-catenin degradation with pyrvinium pamoate (pyr; 10 Ϫ9 M) prevented the ANG II-induced expression of fibronectin, collagen I, and ␤-catenin target genes. ANG II treatment promoted the accumulation of ␤-catenin protein in a time-dependent manner. Because phosphorylation of glycogen synthase kinase-3␤ (GSK-3␤) inhibits ␤-catenin degradation, we further evaluated the effects of ANG II and ANG II plus pyr on p-ser9-GSK-3␤ levels. ANG II-dependent upregulation of ␤-catenin protein levels was correlated with GSK-3␤ phosphorylation. These effects were prevented by pyr. Our data indicate that in M-1 collecting duct cells, the ␤-catenin pathway mediates the stimulation of fibronectin and collagen I in response to AT 1 receptor activation. pyrvinium pamoate; mouse collecting duct cell; tissue homeostasis ANGIOTENSIN II (ANG II) plays a key role in the development and progression of chronic kidney disease (CKD) (27). It has been shown that increased levels of ANG II and renin in renal tubules after subtotal nephrectomy are pathogenically linked to the development of tubulointerstitial injury (10). In particular, alterations in the ANG type 1 (AT 1 ) receptor, angiotensin-converting enzyme 2 (ACE-2), and the newly described (pro)renin receptor precede the development of renal fibrosis (41). Evidence from in vivo studies has shown that AT 1 receptor antagonists ameliorate renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction (17). Furthermore, in vitro studies indicate that ANG II activates renal cells to produce profibrotic factors and extracellular matrix (ECM) proteins (37, 48, 51). These profibrotic factors lead to tubulointerstitial injury and glomerulosclerosis due to excessive accumulation and deposition of ECM components (3, 49), which are the final manifestations of CKD and renal failure (24). In the kidney...

(Pro)renin receptor activation increases profibrotic markers and fibroblast‐like phenotype through MAPK‐dependent ROS formation in mouse renal collecting duct cells

“…CD cells have the predisposition to epithelial–mesenchymal transition . We have shown that ANG II treatment stimulates fibronectin and collagen I, both markers of fibrosis, via β‐catenin pathway in M‐1 CD cells . Here we have shown that prorenin treatment at nanomlar concentrations induces ROS formation and enhance the expression of CTGF, α‐SMA, PAI‐I, fibronectin and collagen I, all markers of fibrosis (Figures and ).…”

“…We have demonstrated that chronic ANG II infusions increase CD renin and prorenin synthesis and secretion despite the suppression of renin expression in juxtaglomerular cells . In addition, we have shown that cultured CD cells undergo to epithelial–mesenchymal transition and have induced expression of fibronectin and collagen I after ANG II treatment …”

AT1 receptor signaling pathways in the cardiovascular system

“…AngII enhances Wnt1 expression, β-catenin nuclear translocation in mouse podocytes, with inhibition of Wnt/β-catenin pathway attenuating podocyte injury (139). β-catenin destabilization reagent also inhibits AngII-induced β-catenin, collagen I, fibronectin and osteopontin in mouse collecting duct cell or kidney of renovascular hypertensive rat (140, 141). Thus, there is accumulating evidence indicating a close relationship between the Wnt/β-catenin pathway and AT1 receptor in regard to cardiovascular remodeling and chronic kidney diseases.…”

Roles of collecting duct renin and (pro)renin receptor in hypertension: mini review

“…However, it has been shown that intratubular Ang II can also promotes tubular fibrosis (Ishidoya et al 1995) and that collecting duct cells have the predisposition to epithelial-mesenchymal transition (Ivanova et al 2008; Butt et al 2007). We demonstrated in vitro evidence that Ang II treatment of collecting duct cells stimulates fibronectin and collagen I, both markers of fibrosis, via β-catenin pathway (Cuevas et al 2014). Further studies are necessary to fully elucidate whether the stimulation of tubular fibrosis during intrarenal RAS activation is dependent or independent of an Ang II-mediated mechanism, i.e., the direct activation of the (P)RR by prorenin in the collecting duct.…”