Arginase 2 deficiency mitigates sepsis-associated acute kidney injury by alleviating lipid accumulation

Sepsis-associated acute kidney injury (S-AKI) imposes substantial morbidity and mortality burdens in critically ill populations. This study aimed to construct a spatiotemporal multi-omics atlas of kidneys in a mouse model of S-AKI using spatial metabolomics and proteomics, and to explore potential therapeutic targets for S-AKI.

A spatiotemporal multi-omics atlas of S-AKI mouse kidneys was constructed using spatial metabolomics and proteomics. Arginine metabolism was evaluated via L-arginine supplementation. ARG2 was inhibited by nor-NOHA or renal tubule-specific knockdown. Kidney injury was assessed by histopathology, real-time glomerular filtration rate (RT-GFR), serum serum urea nitrogen (BUN), and injury markers. RNA-seq and serum metabolomics elucidated nor-NOHA's mechanism, with in vivo verification of pathway activation and lipid reduction. In vitro studies used ARG2 KO renal primary tubular epithelial cells (RPTCs) and kidney organoids.

Arginine metabolism played a crucial role, but L-arginine supplementation did not improve renal function. ARG2 was significantly upregulated in proximal and distal tubules of the renal outer medulla and in macrophages. Treatment with the arginase inhibitor nor-NOHA or knockdown of ARG2 in renal tubules significantly alleviated kidney injury, as evidenced by reduced tubular injury, increased RT-GFR, decreased BUN, and reduced injury markers. RNA-seq and serum metabolomics showed that nor-NOHA significantly reduced lipid accumulation in renal tubules and serum, with significant enrichment of the peroxisome proliferator-activated receptor (PPAR) pathway centered around PPARγ. In vivo experiments confirmed pathway activation and alleviation of lipid accumulation. In vitro experiments using RPTCs from ARG2 knockout mice and human kidney organoid model revealed that ARG2 knockout restored PPARγ expression and reduced tubular lipid accumulation.

Inhibiting ARG2 in renal tubules during S-AKI may alleviate lipid accumulation and kidney injury by activating PPARγ, providing a new therapeutic strategy.

Spatiotemporal multi-omics analysis constructed a detailed atlas of S-AKI kidneys, revealing the regional specificity of metabolic and protein expression in different kidney regions during the progression from sepsis to S-AKI. Arginine metabolism plays a key role in the pathogenesis of S-AKI, with arginine levels continuously decreasing in S-AKI and significantly correlating with renal function. In S-AKI, ARG2 expression increases, mainly localizing to renal tubular cells and macrophages. Renal tubule-specific ARG2 knockdown reduces renal tubular lipid accumulation and kidney injury in S-AKI, likely playing an important role by regulating PPARγ to affect lipid accumulation. The kidney organoids with ARG2 knockout further confirmed the key role of ARG2 in S-AKI, providing a new therapeutic target for S-AKI treatment.