Diabetic nephropathy (DN) is characterized by chronic low-grade renal inflammatory responses, which greatly contribute to
disease progression. Abnormal
glucose metabolism disrupts renal lipid metabolism, leading to
lipid accumulation, nephrotoxicity, and subsequent aseptic renal interstitial
inflammation. In this study, we investigated the mechanisms underlying the renal
inflammation in diabetes, driven by
glucose-
lipid metabolic rearrangement with a focus on the role of
acetyl-CoA synthetase 2 (ACSS2) in
lipid accumulation and renal tubular injury. Diabetic models were established in mice by the injection of
streptozotocin and in human renal tubular epithelial HK-2 cells cultured under a high
glucose (HG, 30 mmol/L) condition. We showed that the expression levels of ACSS2 were significantly increased in renal tubular epithelial cells (RTECs) from the diabetic mice and human diabetic kidney biopsy samples, and ACSS2 was co-localized with the pro-inflammatory
cytokine IL-1β in RTECs. Diabetic ACSS2-deficient mice exhibited reduced renal tubular injury and inflammatory responses. Similarly, ACSS2 knockdown or inhibition of ACSS2 by ACSS2i (10 µmol/L) in HK-2 cells significantly ameliorated HG-induced
inflammation, mitochondrial stress, and
fatty acid synthesis. Molecular docking revealed that ACSS2 interacted with
Sirtuin 1 (
SIRT1). In HG-treated HK-2 cells, we demonstrated that ACSS2 suppressed
SIRT1 expression and activated
fatty acid synthesis by modulating SIRT1-carbohydrate responsive
element binding protein (ChREBP) activity, leading to mitochondrial oxidative stress and
inflammation. We conclude that ACSS2 promotes mitochondrial oxidative stress and renal tubular
inflammation in DN by regulating the SIRT1-ChREBP pathway. This highlights the potential therapeutic value of pharmacological inhibition of ACSS2 for alleviating renal
inflammation and dysregulation of
fatty acid metabolic homeostasis in DN. Metabolic
inflammation in the renal region, driven by
lipid metabolism disorder, is a key factor in renal injury in diabetic nephropathy (DN).
Acetyl-CoA synthetase 2 (ACSS2) is abundantly expressed in renal tubular epithelial cells (RTECs) and highly upregulated in diabetic kidneys. Deleting ACSS2 reduces renal
fatty acid accumulation and markers of renal tubular injury in diabetic mice. We demonstrate that ACSS2 deletion inhibits ChREBP-mediated
fatty acid lipogenesis, mitochondrial oxidative stress, and inflammatory response in RTECs, which play a major role in the progression of diabetic renal tubular injury in the kidney. These findings support the potential use of ACSS2 inhibitors in treating patients with DN.