Diabetic kidney disease (DKD) is a major complication of type 2 diabetes mellitus (T2DM) and a leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). DKD is characterized by chronic hyperglycemia, hypertension, and systemic inflammation that impose deleterious effects on podocytes and proximal tubular cells (PTCs), which contributes to the onset and progression of DKD. Emerging evidence implicates the non-canonical NF-kB signaling pathway, induced by tumor necrosis factor (TNF)-related weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14), in promoting these pathological features of DKD. However, despite advancements improving the outlook for DKD management, there remain essential gaps in understanding the molecular mechanisms that drive the pathophysiology of chronic low-grade inflammation and its contribution to progressive declining kidney function. The central hypothesis of this proposal is that hyperglycemia triggers impaired autophagy that exacerbates chronic inflammation in DKD through TWEAK-Fn14 signaling, which has distinct features in podocytes, PTCs, and kidney fibroblasts. This proposal seeks to 1) Define crosstalk signaling mechanisms in renal cells between autophagy and NF-kB under high glucose conditions, 2) Determine the impact of Fn14 ablation in attenuating kidney inflammation during DKD progression in mice, and 3) Determine the effectiveness of non-canonical NF-kB inhibitors in preventing inflammation and fibrosis in high glucose conditions. Successful completion of this study will elucidate the crosstalk mechanisms by which the autophagy and TWEAK/Fn14 signaling axis modulate chronic inflammation in DKD, identify potential therapeutic candidates, and address significant gaps in our understanding of persistent low-grade inflammation and declining kidney function in DKD.