IKKα aggravates renal fibrogenesis by positively regulating the Wnt/β‐catenin pathway

Abstract

AKI (acute kidney injury) with maladaptive repair plays exacerbated role in renal fibrosis characterized by tubulointerstitial fibrosis. Previously, we reported that IKKα contributed to kidney regeneration and inhibited inflammation. Here, we first identified the role and mechanism of IKKα on TGF-β1-induced fibrosis in human tubular epithelial cells and fibrotic kidneys. IKKα was up-regulated in kidney tubular epithelium in unilateral ureteral obstruction (UUO) and unilateral ischemic reperfusion injury (UIRI) mice. Immunohistochemical staining showed that IKKα was positively correlated with the extent of kidney fibrosis in tissue biopsies from chronic kidney disease (CKD) patients. Compared with wild-type controls, Ksp-IKKα À/À mice exhibited inactivated Wnt/β-catenin pathway, decreased serum creatinine and interstitial fibrosis in the kidney after IRI. In TGF-β1-stimulated human tubular epithelial cells, IKKα overexpression enhanced β-catenin nuclear translocation. Blocking IKKα by siRNA specifically suppressed β-catenin activation and downstream profibrotic genes such as fibronectin and α-smooth muscle actin (α-SMA). Taken together, our study demonstrated that IKKα aggravated renal fibrogenesis by activating Wnt/β-catenin signalling pathway, providing a new target for the treatment of kidney fibrosis.

Colorectal cancer cells secreting DKK4 transform fibroblasts to promote tumour metastasis

“…Regardless of the origin, increasing evidence strongly supports that the resultant myofibroblasts share the same properties and signalling cascade events that lead to their formation. The activity of Wnt/β-catenin signalling is implicated in the fibrogenesis of multiple organs [ 45 , 46 ]. The increased nuclear accumulation of β-catenin was observed in human tissue samples from systemic scleroderma [ 47 ], idiopathic pulmonary fibrosis [ 48 ], and liver cirrhosis [ 49 ].…”

Epithelial–mesenchymal plasticity in kidney fibrosis

“…Several lines of evidence have reported that EMT of TECs plays a crucial role kidney fibrogenesis (Hu, Tang, Liu, Hu, & Pan, 2022; Kandel & Singh, 2022; Wang et al, 2022; Zhang, Xing, & Zhao, 2021). Initiation of fibrosis occurs when the toxins/stimuli cause TECs and kidney tissue to damage or dysfunction (Jorgacevic et al, 2022; Zhang et al, 2023). As expected, mechanisms responsible for such toxins/stimuli‐induced detrimental injury are mainly inflammation and repairing process (Ovadya & Krizhanovsky, 2015; Yang et al, 2021).…”