The deficient of eNOS-NO pathway exacerbates kidney dysfunction via inflammasome activation in diabetic kidney disease
Background: Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease. We have reported that inflammasome activation is involved in the pathogenesis of kidney disease and that the disruption of the endothelial nitric oxide synthase (eNOS)-nitric oxide (NO) pathway promotes inflammasome activation and renal interstitial inflammation in hypertensive and aging kidney models. Endothelial dysfunction, which is involved in the pathogenesis of renal injury, may regulate inflammasome activation. However, it is not known whether endothelial dysfunction promotes the progression of DKD via inflammasome activation. Methods: Apoptosis-associated speck-like protein (ASC) is one of the components constituting the inflammasome. We crossed eNOS-deficient mice (eNOSKO) with ASC-deficient mice to create eNOS-ASC-double-deficient mice (eNOS-ASC-DKO). C57BL / 6 (WT), eNOSKO and eNOS-ASC-DKO were administered streptozotocin (STZ) to induce diabetes. Urine storage and blood pressure measurements were taken in these groups. Eight weeks after the onset of diabetes, they were sacrificed and examined. Tissue damage was examined by PAS staining, Masson staining, and tissue immunohistochemistry. Results: The exacerbation of glomerular lesions were observed in eNOSKO-STZ mice. Kidney injury molecule-1 (KIM-1) positive impaired proximal tubules increased as well. The interstitial fibrosis was significantly increased. These changes were rescued by ASC deficiency. In addition, macrophage infiltrated into the glomeruli in eNOS-deficient mice. Interestingly, these inflammatory cell infiltrations were suppressed in eNOS-ASC-DKO-STZ mice. Conclusions: This study used a DKD model to demonstrate the impact of endothelial dysfunction on chronic inflammation. The results indicate that controlling inflammasome activation may inhibit the progression of kidney disease.