Exploring inflammatory and fibrotic mechanisms driving diabetic nephropathy progression

Diabetic nephropathy (DN) remains a leading cause of end-stage renal disease, with inflammation and fibrosis serving as pivotal drivers of disease progression. Chronic hyperglycemia induces oxidative stress, activates immune pathways, and promotes extracellular matrix (ECM) accumulation, leading to irreversible kidney damage. Inflammatory cytokines contribute to DN progression, such as tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1), IL-6, and IL-17. Moreover, chemokines, their receptors, and adhesion molecules are critically involved in the progression of inflammation during the development of DN. On the other hand, several renal cell types contribute to the fibrotic process of DN by either producing ECM components directly or secreting profibrotic mediators that stimulate fibroblast activation. Fibroblasts, immune cells, and endothelial cells play pivotal roles in mediating fibrosis. Emerging evidence highlights the critical role of inflammatory and fibrotic signaling pathways in DN progression. The activation of the NF-κB, JAK-STAT, and NLRP3 inflammasome pathways contributes to sustained inflammation by promoting proinflammatory cytokine release and immune cell infiltration. Simultaneously, the TGF-β/Smad, Wnt/β-catenin, PI3K/Akt, and MAPK signaling pathways drive fibrosis by inducing ECM deposition and epithelialmesenchymal transition (EMT). Understanding these interconnected pathways provides insights into potential therapeutic targets for mitigating DN progression. In this review, we explore the molecular mechanisms that link inflammation and fibrotic responses to the progression of DN, focusing on signaling pathways, cellular mediators and therapeutic targets.