Adipokine networks in diabetic kidney disease: mechanistic insights and therapeutic implications

Diabetic kidney disease (DKD), the predominant microvascular complication of diabetes mellitus, perpetuates a significant global health and socioeconomic challenge, complicating the pursuit of sustainable renal care. Adipokines, bioactive proteins secreted by adipose tissue that modulate lipid metabolism, function as key modulators potentially integrating systemic metabolic and inflammatory signals with renal pathophysiology Mechanistic investigations reveal that adipokines orchestrate a range of interconnected pathways, which include metabolic dysregulation (characterized by insulin resistance and lipid overload), immune-inflammatory responses (mediated by nuclear factor kappa B [NF-κB], NLR family pyrin domain containing 3 [NLRP3], and chemokine axes), oxidative stress coupled with mitochondrial dysfunction (involving adenosine monophosphate-activated protein kinase [AMPK] and peroxisome proliferator-activated receptor gamma coactivator 1-alpha [PGC-1α], reactive oxygen species [ROS]), endothelial dysfunction, fibrogenesis (driven by transforming growth factor beta [TGF-β]/Smad and epithelial-mesenchymal transition [EMT]), and the imbalance between apoptosis and autophagy. Protective adipokines such as adiponectin, irisin, and vaspin may mitigate harmful signaling, whereas leptin, resistin, visfatin, and chemerin could amplify injury through pro-inflammatory, pro-fibrotic, and lipotoxic pathways. Both circulating and urinary levels of adipokines may correlate with proteinuria, which suggests their potential utility in early detection, risk stratification, or therapeutic monitoring, although further validation is required.Emerging pharmacological, genetic, and lifestyle interventions may modulate adipokine networks to confer renal protection. The integration of multi-omics approaches, single-cell analysis, and spatial profiling with models that closely mimic human physiology is essential for identifying key signaling nodes, validating biomarkers, and developing precision-targeted therapies. Collectively, a detailed, network-oriented understanding of lipid-regulating adipokines could support efforts toward the development of personalized prevention and treatment strategies in DKD.