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.

Keywords: CKD; GSK3; Lithium; Oxidative stress; podocytopathy.

Figure 1:. Protein three-dimensional structure modeling of GSK3β.

The full-length three-dimensional protein structure of GSK3β was based on and SWISS-MODLE (https://swissmodel.expasy.org/interactive). Views of the three- dimensional model of human GSK3β.

Figure 2:. Single-cell database analysis reveals widespread expression of GSK3β across kidney cell populations.

GSK3β is predominantly expressed in various kidney cell types, including podocytes, mesangial cells, and renal tubular epithelial cells. A post hoc analysis was performed on the single nucleus RNA sequencing (snRNAseq) transcriptome of human kidneys based on the Wu and Uchimura et al. Healthy Adult Kidney Dataset (RBK RID: 14–4KPM) that is publicly available from Kidney Interactive Transcriptomics (https://humphreyslab.com/SingleCell/) reveals the mRNA expression of GSK3B in various kidney cells (A, B) . CNT, connecting tubule; DCT, distal convoluted tubule; EC, endothelial cell; IC-A, alpha intercalated cell; IC-B, beta intercalated cell; LH (AL), loop of henle (ascending limb); LH (DL), loop of henle (descending limb); PC, collecting duct principal cell; PT (S1), proximal tubular (Segment 1); PT (S2), proximal tubular (Segment 2); PT (S3), proximal tubular (Segment 3)

Figure 3:. GSK3β is highly conserved in various organisms.

Amino acid sequence alignment analysis of GSK3β in various organisms. Multiple sequence alignments were analyzed using the DNAMAN analysis software package (DNAMAN version 6.0).

Figure 4:. Schematic of GSK3β signaling pathways.

Following activation, GSK3β triggers a variety of signaling pathways, including Wnt/β-catenin pathway, NRF2 pathway, NF-κB pathway, and TGF-β/Smad pathway, which are likely implicated in the regulation of cellular function and homeostasis by GSK3β. Beyond these pathways, GSK3β plays an important role in cytoskeletal remodeling and mitochondrial regulation, impacting cellular motility, structural integrity and viability. AKI, acute kidney injury; CBP, CREB-binding proteins; CK1, casein kinase 1; CREB, cAMP response element-binding protein; CRMP2, collapsin response mediator protein 2; MPT, mitochondria permeability transition; NRF2, NF-E2-related factor 2; P, phosphorylation; Ub, ubiquitin; VDAC, voltage-dependent anion channel. The diagram was drawn by Figdraw.

Figure 5:. 2D chemical structure of the GSK3β inhibitor.

(A) 2D chemical structure of lithium chloride. (B) 2D chemical structure of TDZD-8. (C) 2D chemical structure of SB216763. (D) 2D chemical structure of Tideglusib. The 2D chemical structure were download from Pubchem (https://pubchem.ncbi.nlm.nih.gov/).