SIRT2 in Diabetic Kidney Disease: Multifaceted Regulatory Roles and Therapeutic Challenges.

Diabetic kidney disease (DKD) is a significant microvascular complication of diabetes, characterized by a complex interplay between metabolic dysregulation and chronic inflammation. This review methodically elucidates the pivotal role of the deacetylase sirtuin 2 (SIRT2) within this pathological network. SIRT2, a nicotinamide adenine dinucleotide dependent metabolic sensor, deacetylates multiple substrates to regulate renal intrinsic cell functions (eg, podocytes and tubular epithelial cells). It suppresses nuclear factor kappaB and nod-like receptor protein 3 inflammasome pathways, modulates macrophage polarization, and influences "metabolic memory". However, these critical functions exhibit cell- and context-dependent specificity. For instance, in podocytes, SIRT2 maintains cytoskeletal stability by deacetylating α-tubulin. Conversely, in certain models of renal tubular injury, SIRT2 may exacerbate damage, underscoring its highly context-dependent function. Consequently, the targeting of SIRT2 (including the development of selective modulators and the exploration of combination therapies with existing treatments such as sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists) is considered a promising therapeutic strategy. Notwithstanding, SIRT2-targeted therapies face a multitude of challenges, including functional duality, tissue-specific delivery, and clinical translation. This necessitates meticulous evaluation for clinical application. Future efforts should leverage cutting-edge technologies to deepen mechanistic understanding and advance biomarker-guided precision medicine, thereby providing a theoretical foundation for novel DKD therapies.