4-OR: Oxidative Phosphorylation in Kidney-Resident Macrophages Aggravates the Progression of Diabetic Kidney Disease

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Introduction and Objective: Oxidative phosphorylation (OXPHOS) is a hallmark alteration in the diabetic kidney. However, it remains unclear whether this change occurs in kidney-resident macrophages (KRMs) and how this condition contributes to the progression of diabetic kidney disease (DKD). Methods: We investigated OXPHOS-related transcriptomic changes in KRMs within diabetic kidneys using single-cell RNA sequencing data derived from human kidneys. We assessed OXPHOS expression in KRMs and its associated renal immunological alterations in DKD mouse models induced by high-fat diet, streptozotocin, and adenine-mixed diet, particularly under conditions of augmented inflammation. Results: Single-cell RNA sequencing analysis revealed increased OXPHOS alteration in KRMs of diabetic kidneys compared to nondiabetic controls. These findings were validated through the examination of OXPHOS-related protein expression in biopsy-proven diabetic nephropathy samples, where enhanced OXPHOS expression correlated with accelerated DKD progression. In DKD mouse models, elevated OXPHOS expression in diabetic KRMs promoted T cell infiltration into the kidneys through the overexpression of chemokine ligands and proinflammatory cytokines. Inhibition of OXPHOS reduced T cell infiltration and mitigated the decline in renal function. Conclusion: Elevated OXPHOS expression in KRMs is a defining feature of diabetic kidneys, fostering a proinflammatory milieu through T cell infiltration. Targeting OXPHOS in KRMs may serve as a potential therapeutic strategy for DKD. Disclosure H. Yoon: None. P. Park: None. J. Hwang: None. M. Hong: None. B. Jang: None. C. Kang: None. D. Yun: None. S. Han: None. Funding Korea Health Industry Development Institute (HI23C1531)

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