SB‐216763, a GSK‐3β inhibitor, protects against aldosterone‐induced cardiac, and renal injury by activating autophagy

Abstract

Cardiovascular and renal inflammation induced by Aldosterone (Aldo) plays a pivotal role in the pathogenesis of hypertension and renal fibrosis. GSK‐3β contributes to inflammatory cardiovascular and renal diseases, but its role in Aldo‐induced hypertension, and renal damage is not clear. In the present study, rats were treated with Aldo combined with SB‐216763 (a GSK‐3β inhibitor) for 4 weeks. Hemodynamic, cardiac, and renal parameters were assayed at the indicated time. Here we found that rats treated with Aldo presented cardiac and renal hypertrophy and dysfunction. Cardiac and renal expression levels of molecular markers attesting inflammation and fibrosis were increased by Aldo infusion, whereas the treatment of SB‐216763 reversed these alterations. SB‐216763 suppressed cardiac and renal inflammatory cytokines levels (TNF‐a, IL‐1β, and MCP‐1). Meanwhile, SB‐216763 increased the protein levels of LC3‐II in the cardiorenal tissues as well as p62 degradation, indicating that SB‐216763 induced autophagy activation in cardiac, and renal tissues. Importantly, inhibition of autophagy by 3‐MA attenuated the role of SB‐216763 in inhibiting perivascular fibrosis, and tubulointerstitial injury. These data suggest that SB‐216763 protected against Aldo‐induced cardiac and renal injury by activating autophagy, and might be a therapeutic option for salt‐sensitive hypertension and renal fibrosis.

Expression of claudin-8 is induced by aldosterone in renal collecting duct principal cells

“…Activation of GSK3 by aldosterone has been recently reported in several studies (22)(23)(24). F7 Figure 7 shows that inhibition of GSK3 by two structurally unrelated pharmacological inhibitors SB216763 (Fig.…”

Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis

“…Numerous studies have shown that GSK-3β activation plays a wide spectrum of important roles in tissue fibrosis (Zhuang et al, 2018;Zeng et al, 2019). SB-216763, a GSK-3β inhibitor, protects against Aldo-induced renal injury by activating autophagy and might be a therapeutic option for renal fibrosis (Zhang et al, 2018b). Substrate competitive inhibitors (SCIs), a novel small molecule GSK-3 inhibitor, is considered to be highly selective and more suitable for clinical practice (Rippin et al, 2020).…”

Targeting the Wnt Signaling Pathway in Liver Fibrosis for Drug Options: An Update

“…GSK-3β inhibition by SB-216763 protected against aldosterone-induced renal and cardiac injuries by activating autophagy. 96 However, for cholestatic liver disease in a mouse model, a study by Zhuang et al . 97 demonstrated that SB-216763 therapy aggravated liver fibrosis.…”