Sphingosine Kinase 2-Mediated Pyroptosis of Renal Tubular Epithelial Cells Contributes to the Progression of Diabetic Nephropathy

Pyroptosis of renal tubular epithelial cells and deposition of interstitial matrix proteins leads to chronic diabetic nephropathy. Recent data suggest that deficiency of sphingosine kinase 2 (SphK2) attenuates acute kidney injury and renal fibrosis. We aim to investigate the role of SphK2 signaling in the pathogenesis of diabetic nephropathy. The protein expression of SphK2 in kidney, especially in renal tubular, was significantly increased in STZ-induced diabetic mice and Leprdb/db mice, compared with control mice. Renal injury and fibrosis, as demonstrated by albumin-to-creatinine ratio, histology and fibronectin deposition, were significantly ameliorated in STZ-induced SphK2-/- or Leprdb/dbSphK2-/- double KO mice relative to control mice. Moreover, administration of ABC294640, the specific inhibitor of SphK2, significantly prevented renal injury and fibrosis in STZ-induced diabetic mice. SphK2 siRNA significantly downregulated fibronectin in renal tubular epithelial cells (NRK52E) cultured by high glucose. Furthermore, the activation of NLRP3 inflammasome and caspase 1, as well as subsequent pyroptosis were significantly inhibited in NRK52E cells transfected with SphK2 siRNA under high glucose condition. In conclusion, SphK2 deficiency attenuates diabetic nephropathy by preventing pyroptosis in renal tubular epithelial cells. Disclosure L. Liang: None. W. Liu: None. W. Cheung: None. W. Ding: None. T. Lan: None. Funding National Natural Science Foundation of China (81870420); Science and Technology Planning Project of Guangdong Province (2017A020211007)