β-Hydroxybutyrate Attenuates Diabetic Kidney Disease Partially Via β-hydroxybutyrylation of Nrf2.

Abstract

Diabetic kidney disease (DKD) is one of the predominant microvascular complications in diabetes. In recent years, the nuclear factor E2-related factor 2 (Nrf2)-mediated anti-oxidative stress pathway is tightly regulated by multiple post-translational modifications, governing its role in countering oxidative stress and DKD pathogenesis. Recent studies have found that the principal constituent of ketone bodies, β-hydroxybutyrate (β-HB), not only serves as an alternative energy source, but also induced lysine β-hydroxybutyrylation (Kbhb), which has various unknown pathophysiological functions. Previous research reports that β-HB activates Nrf2 and then treats DKD, yet its underlying molecular mechanism remains unclear. To explore the mechanism of β-HB induced Kbhb in DKD, β-HB was administered in both in vivo and in vitro. Our results verified that exogenous β-HB supplementation alleviated dysglycolipidemia, inhibited proteinuria and renal dysfunction. Meanwhile, β-HB enhanced Nrf2 Kbhb modification, and activated the Nrf2 signaling to mitigate renal inflammatory-fibrotic injury in diabetes. However, inhibition of Kbhb partially reversed β-HB-mediated Nrf2 activation and nephroprotection. In conclusion, our data reveal that β-HB attenuates DKD, β-HB-induced Nrf2 Kbhb modification may be an important molecular mechanism in the pathogenesis and treatment of DKD.