Morusin ameliorates tubulointerstitial damage in diabetic mice through SIRT1/HIF-1α/IL-16 signaling pathway

Background and purpose: Hypoxia is generally considered the major cause of renal tubular injury. The interaction between Sirtuin 1 (SIRT1) and hypoxia inducible factor 1 subunit alpha (HIF-1α) is a key mediator of hypoxia-induced renal tubular damage. In this study, we identified morusin from a screen of SIRT1 inducers and reported its potential for the treatment of diabetic kidney disease (DKD).

Experimental approach: Intraperitoneal injection of morusin in db/db and STZ-induced diabetic mice was assessed for its effect on tubulointerstitial damage. The expression and acetylation level of HIF-1α were analyzed by immunoblotting or immunostaining. The effects of morusin treatment on hypoxia-induced extracellular matrix (ECM) accumulation, Apoptosis and IL-16 production in HK2 cells were evaluated by immunoblotting. Luciferase reporter gene and ChIP analysis was used to determine whether IL-16 was the target genes of HIF-1α.

Key results: In db/db and STZ-induced mice, morusin treatment alleviated kidney injury and inhibited renal inflammation and fibrosis. Mechanistic analysis using animal models and HK2 cells revealed that morusin treatment upregulated SIRT1 expression by enhancing its stability, and reduced the expression and acetylation levels of HIF-1α as well as expression of its regulated genes, thereby inhibiting ECM accumulation, Apoptosis and IL-16 production. Furthermore, morusin decreased expression of the IL-16 through inhibited HIF-1α binding to the IL-16 promoter.

Conclusion and implications: Our study is the first to demonstrate that morusin ameliorated tubulointerstitial damage in diabetic mice by regulating SIRT1/HIF-1α/IL-16 signaling pathway. Taken together, our findings suggest that morusin is a clinical candidate compound to prevent DKD.

Diabetic kidney disease; Hif-1(; Hypoxia; Morusin; Sirt1.