Sodium Butyrate Ameliorates Diabetic Kidney Disease Partially Through ACSS2/P300-Mediated Histone Butyrylation Pathway

Abstract Background: Studies suggest that sodium butyrate (NaB) can ameliorate glucose and lipid metabolism, as well as renal damage in dabetic kidney disease (DKD) mice, potentially through histone post-translational modifications. Histone butyrylation, an acylation modification induced by butyrate, is facilitated by acetyl-CoA synthetase 2 (ACSS2) and P300. However, the precise role and mechanism of NaB and histone butyrylation in DKD prevention and treatment remain unclear. Purpose: This study aimed to investigate whether NaB improves renal inflammation and fibrosis in DKD through the ACSS2/P300-mediated histone butyrylation pathway. Methods: DKD models were replicated in vivo and in vitro using db/db mice and high glucose-induced mesangial cells, respectively. Intervention methods included NaB/butyryl-CoA, ACSS2 inhibitor/siRNA, adeno-associated virus 9 (AAV9)-mediated ACSS2 overexpression, and A485 (a P300 inhibitor). Assessments included body weight, glucose levels, lipid profile, urinary albumin-to-creatinine ratio (UACR), renal function and pathology, and the expression levels of pan-butyrylation (PanKbu), histone lysine butyrylation (H3K9bu, H3K18bu), and inflammatory and fibrotic cytokines. Results: NaB exhibited antidiabetic effects, reduced serum lipid levels, alleviated UACR, and improved renal function, reducing inflammatory and fibrotic damage in the kidneys of db/db mice. Additionally, PanKbu, H3K9bu, and H3K18bu in kidney tissues of DKD mice and high-glucose-induced mesangial cells were upregulated by NaB or butyryl-CoA in a concentration-dependent manner. Mechanistically, ACSS2 inhibition or knockdown by siRNA hindered, while ACSS2 overexpression facilitated, NaB-induced histone butyrylation and its anti-inflammatory and anti-fibrotic effects. Lastly, A485 re详versed the renal protective effects induced by NaB or butyryl-CoA. Conclusions: This study identifies a novel role for NaB in alleviating DKD and inhibiting the expression of inflammatory and fibrotic genes partially through the ACSS2 and P300-mediated histone butyrylation pathway, suggesting that histone butyrylation may play a significant role in the pathogenesis and treatment of DKD.