Sodium Crotonate Alleviates Diabetic Kidney Disease Partially Via the Histone Crotonylation Pathway

Area of Science:

• Biochemistry
• Nephrology
• Epigenetics

Background:

• Diabetic kidney disease (DKD) is a major diabetes complication driven by inflammation and fibrosis.
• Histone lysine crotonylation (Kcr) is a recently identified post-translational modification with emerging roles in kidney diseases.
• The specific impact of sodium crotonate (NaCr) and NaCr-induced Kcr on DKD pathogenesis is not well understood.

Purpose of the Study:

• To investigate the therapeutic effects of NaCr on DKD.
• To explore the role of NaCr-induced histone Kcr in DKD.
• To elucidate the molecular mechanisms underlying NaCr's protective effects in DKD.

Main Methods:

• Utilized db/db mice and high glucose-induced human tubular epithelial cells (HK-2) models.
• Administered exogenous NaCr and crotonoyl-coenzyme A (Cr-CoA) as intervention agents.
• Assessed histone Kcr levels, DKD indicators, blood glucose, serum lipids, and renal function. Inhibited Acyl-CoA synthetase short-chain family member 2 (ACSS2) and P300 activity.

Main Results:

• NaCr demonstrated significant antidiabetic effects, lowering blood glucose and serum lipids.
• NaCr treatment alleviated renal function and reduced DKD-associated inflammation and fibrosis.
• NaCr induced histone Kcr, specifically histone H3K18 crotonylation (H3K18cr), and these effects were dependent on ACSS2 and P300 activity.

Conclusions:

• NaCr mitigates DKD through both its antidiabetic properties and by inducing histone Kcr via ACSS2 and P300.
• Histone Kcr represents a potential molecular mechanism and therapeutic target for DKD prevention and treatment.
• Further research into Kcr modulation could offer novel strategies for managing diabetic kidney disease.