Defective autophagy in diabetic nephropathy sensitizes podocytes to hyperuricemia induced injury by amplifying inflammasome activation.

Hyperuricemia was associated with faster progression of proteinuria in diabetic nephropathy. However, the underlying mechanisms remained largely unknown. Therefore, this study aimed to explore whether there was a tightly regulated process involved in susceptibility to hyperuricemia under diabetic conditions. We established a diabetes model with hyperuricemia superimposed both in vivo and in vitro. The urinary albumin: creatinine ratio, biomarkers of podocyte damage, markers of inflammasome activation, and autophagosome markers were assessed. In vivo, we found that hyperuricemia aggravated podocyte injury in a diabetic mouse model, manifested by significantly increased albuminuria levels and severe slit diaphragm abnormalities. In addition, significantly excessive inflammasome activation, which might initiate hyperinflammation resulting in podocyte injury, was also found in the glomeruli of the superposed model, accompanied by diminished staining of the autophagosome marker LC3. Accordingly, in vitro, we revealed that high glucose pretreatment induced autophagic deficiency, potentiating inflammasome activation in podocytes. Furthermore, we confirmed that 3-methylamphetamine (3-MA), an inhibitor of autophagy, could aggravate uric acid-induced inflammasome activation in a dose- and time-dependent manner, whereas rapamycin, an inducer of autophagy, could alleviate uric acid-induced inflammasome activation in a dose- and time-dependent manner. Collectively, our data suggested that autophagic deficiency occurring in diabetic kidney disease might sensitize podocytes to hyperuricemia-induced injury by amplifying inflammasome activation. Enhancement of autophagy might provide a promising avenue for ameliorating inflammasome activation and preventing podocyte injury in established diabetic nephropathy.