We showed that IL-1β derived from renal tubular epithelial cells initiates the inflammatory response that promotes salt sensitivity during diabetes. Yet, the intracellular mechanism that mediates IL-1β synthesis by tubular cells is unknown. We hypothesize that high glucose inhibits autophagy in tubular cells resulting in the accumulation of mitochondrial reactive oxygen spices (mtROS) that activate the NLRP3 inflammasome to produce IL-1β. Thirty-week-old db/db mice, a model of type 2 diabetes, and db/+ non-diabetic controls (n=6) were exposed to high salt diet (4% NaCl) for 4 weeks. At the end, mean arterial pressure was higher in db/db vs. db/+ mice (125±7 vs. 104±4 mmHg, P<0.05). db/db mice also displayed higher levels of IL-1β in tubular cells (E-cadherin+) compared to db/+ mice (22±4% vs. 7±2% of IL-1β + E-cadherin + cells, P<0.01 by flow cytometry). We measured two critical components of the autophagy machinery by Western blot. In db/db, we observed reduced LC3B-II expression (49% reduction, P<0.01) and increased p62 (2.7±0.3-fold increase, P<0.001) compared to db/+ mice indicating reduced autophagy. To investigate whether autophagy regulates IL-1β synthesis, we used a primary culture of tubular epithelial cells (TECs) (n=6). TECs exposed to high glucose (15mM) secreted higher levels of IL-1β (58±23 vs. 13±6 pg/ml, P>0.001) and displayed increased caspase-1 and NLRP3 expression compared to TECs exposed to low glucose (5mM). Autophagy analysis revealed low LCB3-II and high p62 suggesting that high glucose suppressed autophagy in tubular cells. This was associated with mtROS accumulation (1.9±0.2-fold increase, P<0.001 by MitoSox Red). We also analyzed mTOR, an inhibitor of autophagy. TECs exposed to high glucose showed higher levels of mTOR phosphorylated at Ser 2448 (a marker of activation) compared to low glucose-treated cells. Blocking mTOR with rapamycin (1μM) restored autophagy in high glucose-treated TECs, reduced caspase-1, NLRP3, and mitochondrial ROS and resulted in low IL-1β secretion. Thus, autophagy inhibition is a critical event behind the high glucose-mediated IL-1β secretion in tubular cells. Restoring autophagy might be a therapeutic target to blunt the inflammatory response that causes salt sensitivity during diabetes.