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

Summary

Using spatial metabolomics and proteomics, the study mapped metabolic and protein changes across kidney regions during sepsis-associated acute kidney injury. ARG2 was increased in renal tubular cells and macrophages, and pharmacologic inhibition or renal tubule-specific knockdown improved renal function and reduced tubular lipid accumulation, apparently through restoration of PPARγ signaling. Human kidney organoids provided additional support for the mechanism.

Key Findings

• ARG2 expression increased predominantly in renal tubular cells and macrophages during sepsis-associated acute kidney injury.
• Nor-NOHA treatment or renal tubule-specific ARG2 knockdown reduced tubular injury, improved real-time glomerular filtration rate, and lowered blood urea nitrogen.
• ARG2 inhibition reduced lipid accumulation through activation or restoration of the PPARγ pathway, with supporting evidence from human kidney organoids.

Clinical Implications

ARG2 inhibition could become a strategy for preventing or treating sepsis-associated acute kidney injury, but safety, selectivity, dosing, and efficacy must be established in clinically relevant animal models and prospective human studies before clinical use.

Limitations

• The central efficacy findings were generated in experimental sepsis models rather than in patients.
• The optimal therapeutic window, tissue selectivity, potential effects on systemic arginine metabolism, and long-term safety of ARG2 inhibition were not established.

Future Directions

Future studies should validate ARG2 inhibition in multiple clinically relevant sepsis models, define therapeutic timing and dosing, assess effects on host defense and systemic metabolism, and determine whether ARG2-related signatures identify patients most likely to benefit.