Glycogen synthase kinase 3β: a key player in progressive chronic kidney disease.

Abstract

Chronic kidney disease (CKD) is a serious medical condition that poses substantial burdens on patients, families, healthcare systems, and society as a whole. It is characterized by progressive kidney damage and loss of function in the kidney, often compounded by underlying conditions such as diabetes, hypertension, and autoimmune diseases. Glycogen synthase kinase 3 beta (GSK3β), a highly conserved serine/threonine kinase originally implicated in insulin signaling, has emerged as a convergent point of multiple pathways implicated in the pathogenesis and progression of CKD. In the kidney, GSK3β regulates cell fate across diverse cells, including podocytes, mesangial cells, and renal tubular cells, through its interactions with key signaling pathways such as Wnt/β-catenin, NF-κB, Nrf2, PI3K/Akt, and cytoskeleton remodeling pathways. Evidence suggests that dysregulation of GSK3β is closely associated with pathological changes in the kidney, including podocyte injury, mesangial expansion, interstitial fibrosis, and tubular atrophy, which collectively drive chronic kidney destruction. In CKD, GSK3β is overexpressed and thus hyperactive in kidney cells. This sustained hyperactivity perpetuates oxidative stress and profibrotic signaling, particularly in renal tubular cells, thus accelerating the transition from acute kidney injury to CKD. Pharmacological targeting of GSK3β with selective inhibitors has shown promise in preclinical models, by reducing kidney injury, attenuating renal fibrosis, and promoting renal recovery, positioning GSK3β as a potential therapeutic target for CKD. This review highlights recent advances in understanding the molecular and cellular mechanisms through which GSK3β contributes to CKD and underscores its potential as a therapeutic target for various chronic renal diseases.