Wnt/β-Catenin Signaling Promotes Renal Interstitial Fibrosis

Abstract

Wnts compose a family of signaling proteins that play an essential role in kidney development, but their expression in adult kidney is thought to be silenced. Here, we analyzed the expression and regulation of Wnts and their receptors and antagonists in normal and fibrotic kidneys after obstructive injury. In the normal mouse kidney, the vast majority of 19 different Wnts and 10 frizzled receptor genes was expressed at various levels. After unilateral ureteral obstruction, all members of the Wnt family except Wnt5b, Wnt8b, and Wnt9b were upregulated in the fibrotic kidney with distinct dynamics. In addition, the expression of most Fzd receptors and Wnt antagonists was also induced. Obstructive injury led to a dramatic accumulation of beta-catenin in the cytoplasm and nuclei of renal tubular epithelial cells, indicating activation of the canonical pathway of Wnt signaling. Numerous Wnt/beta-catenin target genes (c-Myc, Twist, lymphoid enhancer-binding factor 1, and fibronectin) were induced, and their expression was closely correlated with renal beta-catenin abundance. Delivery of the Wnt antagonist Dickkopf-1 gene significantly reduced renal beta-catenin accumulation and inhibited the expression of Wnt/beta-catenin target genes. Furthermore, gene therapy with Dickkopf-1 inhibited myofibroblast activation; suppressed expression of fibroblast-specific protein 1, type I collagen, and fibronectin; and reduced total collagen content in the model of obstructive nephropathy. In summary, these results establish a role for Wnt/beta-catenin signaling in the pathogenesis of renal fibrosis and identify this pathway as a potential therapeutic target.

Sonic hedgehog signaling in kidney fibrosis: a master communicator

“…For instance, besides Shh signaling pathway, TGF-β1, Wnt/β-catenin and Notch pathways are well recognized to play crucial roles in the evolution of renal fibrosis in CKD (Bielesz et al, 2010; He and Dai, 2015; He et al, 2009; Tan et al, 2014; Zhou et al, 2016). However, the role of Shh signaling is quite unique in this process in that it specifically targets interstitial cells, while it is mainly produced by the injured tubules.…”

Potential cross-talk between (pro)renin receptors and Wnt/frizzled receptors in cardiovascular and renal disorders

“…Aberrant activation of these pathways has led to heart fibrosis, renal fibrosis, glomerulosclerosis, cystic disease and diabetic nephropathy. 6,112,[130][131][132][133] Overexpression of the (P)RR in the rat and mouse resulted in hypertension and fibrotic effects. 91,111,130 This raises several questions.…”

“…131,133 Impaired Wnt/PCP signaling is associated with abnormal kidney repair. 31 As noted above, (P)RR blockade inhibited the development and progression of glomerulosclerosis in Ang-II type 1a receptor-deficient diabetic mice, while RAS inhibitors only slowed the progression of diabetic nephropathy.…”

Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy

“…Documented studies suggest that the presence of either retinopathy or nephropathy may contribute to the development of the other, especially in type 1 diabetic patients [12]. More importantly, WNT signalling has been shown to be a key regulator of kidney development [13] and has been implicated in certain kidney diseases [14][15][16]. It is reasonable to hypothesise that the WNT signalling pathway is implicated in the pathogenesis of diabetic nephropathy.…”