Short-Chain Fatty Acids Prevent Diabetic Nephropathy In Vivo and In Vitro

Abstract

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). Over the past decade, the gut microbiota metabolites—short-chain fatty acids (SCFAs), have emerged as new therapeutic targets of systemic inflammatory diseases and kidney injury such as acute kidney injury (AKI) via GPRs-β-arrestins signaling pathway and histone deacetylase-inhibiting (HDACi) properties. However, it is unclear whether SCFAs might prevent DN. Therefore, we evaluated the role and mechanism of the three main SCFAs (acetate, propionate, and butyrate) in streptozotocin (STZ) and high-fat diet (HFD)-induced type 2 diabetes (T2D) and DN mouse model in vivo and in high glucose-induced mouse glomerular mesangial cells (GMCs) and human proximal renal tubular epithelia cells in vitro. Our results found that exogenous SCFAs administration, especially butyrate, protected from experimental T2D, preventing the renal dysfunction and inhibiting oxidative stress and NF-κB inflammatory signaling in vivo. The GPR43 expression decreased, however, β-arrestin-2 expression increased in both high glucose-stimulated renal intrinsic cells and in DN kidney tissue. We hypothesized that SCFAs-mediated GPR43-β-arrestin-2 signaling might modulate kidney injury. GPR43 was over-expressed or suppressed by transfection with a GPR43 expressing vector or siRNA-GPR43 respectively. Exogenous SCFAs-mediated the anti-oxidative stress and anti-inflammatory effects were significantly facilitated or imitated by over-expression GPR43 or GPR43 agonist, but which were inhibited by siRNA-GPR43. Specifically, co-IP revealed that butyrate regulated the interaction between I-κBα and β-arrestin-2 via GPR43. Overall, this is the first observation of the potential therapeutic role of SCFAs in DN, we demonstrated that SCFAs improved STZ and HFD-induced renal dysfunction and inhibited NF-κB activation through GPR43-β-arrestin-2 signaling, suggesting a likely mechanism for SCFAs-mediated therapeutic effect in DN. Disclosure W. Huang: None. Y. Xu: None. Y. Xu: None. L. Zhou: None. C. Gao: None.