Permissive effect of GSK3β on profibrogenic plasticity of renal tubular cells in progressive chronic kidney disease

Abstract

Renal tubular epithelial cells (TECs) play a key role in renal fibrogenesis. After persistent injuries that are beyond self-healing capacity, TECs will dedifferentiate, undergo growth arrest, convert to profibrogenic phenotypes, and resort to maladaptive plasticity that ultimately results in renal fibrosis. Evidence suggests that glycogen synthase kinase (GSK) 3β is centrally implicated in kidney injury. However, its role in renal fibrogenesis is obscure. Analysis of publicly available kidney transcriptome database demonstrated that patients with progressive chronic kidney disease (CKD) exhibited GSK3β overexpression in renal tubulointerstitium, in which the predefined hallmark gene sets implicated in fibrogenesis were remarkably enriched. In vitro, TGF-β1 treatment augmented GSK3β expression in TECs, concomitant with dedifferentiation, cell cycle arrest at G2/M phase, excessive accumulation of extracellular matrix, and overproduction of profibrotic cytokines like PAI-1 and CTGF. All these profibrogenic phenotypes were largely abrogated by GSK3β inhibitors or by ectopic expression of a dominant-negative mutant of GSK3β but reinforced in cells expressing the constitutively active mutant of GSK3β. Mechanistically, GSK3β suppressed, whereas inhibiting GSK3β facilitated, the activity of cAMP response element-binding protein (CREB), which competes for CREB-binding protein, a transcriptional coactivator essential for TGF-β1/Smad signaling pathway to drive TECs profibrogenic plasticity. In vivo, in mice with folic acid-induced progressive CKD, targeting of GSK3β in renal tubules via genetic ablation or by microdose lithium mitigated the profibrogenic plasticity of TEC, concomitant with attenuated interstitial fibrosis and tubular atrophy. Collectively, GSK3β is likely a pragmatic therapeutic target for averting profibrogenic plasticity of TECs and improving renal fibrosis.

Key role for EphB2 receptor in kidney fibrosis

“…Whether this pathway also regulates EphB2 in the kidney during injury is not investigated yet. Interestingly, GSK-3β has been recently implicated in the pathogenesis of kidney injury [ 35 ]. On the other hand, it is likely that up-regulation/activation of EphB2 upon kidney injury may aggravate kidney cell injury, death, and EMT and thereby causing renal fibrosis via multiple pathways, including potentiation of NF-κB-mediated inflammation response, activation of TGFβ1/Smad3-mediated EMT and other pathways, as indicated by the NanoString gene expression and verified by the signaling assessment in the present study.…”

Folic acid‐induced animal model of kidney disease

“…19,21,47,48 However, this article will focus on a very popular kidney disease animal model, the folic acid (FA)-induced rodent model involving the use of both mouse and rat. [49][50][51][52][53] A comparison of the FA model with other chemically induced kidney injury animal models is given in Table 1.…”

Myeloid PTEN deficiency aggravates renal inflammation and fibrosis in angiotensin II‐induced hypertension

“…Glycogen synthase kinase 3β (GSK‐3β) is a serine/threonine‐protein kinase that functions as an integration point for multiple cellular pathways including PTEN/PI3K/AKT signaling, which are involved in glycogen biosynthesis, inflammation, mitochondrial dysfunction, and apoptosis (Beurel et al, 2015; Doble & Woodgett, 2003). Recent studies have shown that GSK‐3β plays an important role in the development of renal fibrosis (B. Chen et al, 2021; Lu et al, 2019). As PTEN regulates GSK‐3β activities via PI3K, it will be interesting to examine if PTEN/GSK‐3β signaling pathway is involved in AngII‐induced renal inflammation and fibrosis in the future study.…”