Lupus Nephritis: Glycogen Synthase Kinase 3β Promotion of Renal Damage Through Activation of the NLRP3 Inflammasome in Lupus‐Prone Mice

Abstract

Objective Glycogen synthase kinase 3β (GSK-3β) has been demonstrated to be involved in immune and inflammatory responses via multiple signaling pathways, leading to the production of proinflammatory cytokines. The purpose of this study was to investigate the role of GSK-3β in the pathogenesis of lupus nephritis in 2 mouse models. Methods Thiadiazolidinone 8 (TDZD-8), a selective inhibitor of GSK-3β, was administered intraperitoneally to 12-week-old MRL/lpr mice for 8 weeks or to 22-week-old (NZB × NZW)F1 mice for 12 weeks. The expression of GSK-3β and NLRP3 inflammasome components was analyzed. Proteinuria, biochemical parameters, proinflammatory cytokines, anti–double-stranded DNA (anti-dsDNA) antibody levels, and renal pathology were examined. In vitro, the effect of GSK-3β–directed small interfering RNA (siRNA) on NLRP3 inflammasome activation was evaluated in bone marrow–derived macrophages (BMMs) from the mice and in the J774A.1 macrophage cell line. Results The incidence of severe proteinuria and renal inflammation was significantly attenuated in both models, with a significant reduction in anti-dsDNA antibody production, immune complex deposition in the kidney, and circulating proinflammatory cytokine levels. TDZD-8 inhibited the activation of GSK-3β and caspase 1, with a concomitant decrease in interleukin-1β (IL-1β) synthesis. In vitro, GSK-3β siRNA transfection of mouse BMMs and the J774A.1 cell line with GSK-3β siRNA inhibited the expression of GSK-3β, the activation of caspase 1, and the production of IL-1β. Conclusion These results show that GSK-3β promotes lupus nephritis at least partly by activating the NLRP3/IL-1β pathway. The linking of GSK-3β to the NLRP3/IL-1β pathway is a novel observation in our study. Our results suggest that the GSK-3β/NLRP3/IL-1β pathway may be a potential therapeutic target for lupus in humans.

The β isoform of GSK3 mediates podocyte autonomous injury in proteinuric glomerulopathy

“…Converging evidence recently points to glycogen synthase kinase (GSK) 3 as a novel therapeutic target for podocytopathy and proteinuria . In accordance with this, blockade of GSK3 has been shown to attenuate proteinuria, podocyte injury, and glomerulosclerosis in a number of experimental glomerular diseases, including diabetic nephropathy , lupus nephritis , and podocytopathy elicited by adriamycin (ADR) or LPS . GSK3 is a highly conserved, ubiquitously expressed, and constitutively active multitasking serine/threonine protein kinase, situated at the nexus of a multitude of essential pathways in the complex cell signalling network and acting on a multitude of cognate substrates, including NFκB, β‐catenin, paxillin, cyclophilin F (Cyp‐F), and cyclin D1 .…”

Stressed and Inflamed, Can GSK3 Be Blamed?

“…Caspase-1 deficiency decreased chronic restraint stress-induced depression-like behaviors [52]. GSK3β activates the NLRP3/IL-1β pathway in lupus nephritis [53]. Psychological stress-induced activation of GSK3β leads to activation of the NLRP3/IL-1β pathway [15,54].…”

What is damaging the kidney in lupus nephritis?

“…IFN has multiple detrimental effects on the kidneys including vascular rarefaction and injury to glomerular parietal cells and podocytes (35–36). Once tissue injury occurs, soluble products released from injured cells amplify the inflammatory response by stimulating extracellular and intracellular innate immune receptors (37–41). Podocytes, for example, are sensitive to TLR-mediated signals and other inflammatory mediators such as NO, which induce foot process effacement and podocyte loss (42).…”