Podocyte-specific Nlrp3 inflammasome activation promotes diabetic kidney disease.

Efficient therapies for diabetic kidney disease (DKD), now the leading cause of kidney failure, are lacking. One hallmark of DKD is sterile inflammation (inflammation in absence of microorganisms), but the underlying molecular mechanisms remain poorly understood. The NLRP3 inflammasome (innate immune system receptors and sensors regulating activation of caspase-1) is a mechanism of sterile inflammation known to be activated by metabolic stimuli and reactive metabolites associated with DKD, including inflammasome activation in podocytes. However, whether NLRP3 inflammasome activation in podocytes contributes to sterile inflammation and glomerular damage in DKD remains unknown. Here, we found that kidney damage, as reflected by increased albuminuria, glomerular mesangial expansion and glomerular basement membrane thickness was aggravated in hyperglycemic mice with podocyte-specific expression of an Nlrp3 gain-of-function mutant (Nlrp3A350V). In contrast, hyperglycemic mice with podocyte-specific Nlrp3 or Caspase-1 deficiency showed protection against DKD. Intriguingly, podocyte-specific Nlrp3 deficiency was fully protective, while podocyte-specific caspase-1 deficiency was only partially protective. Podocyte-specific Nlrp3, but not caspase-1 deficiency, maintained glomerular autophagy in hyperglycemic mice, suggesting that podocyte Nlrp3 exerts both canonical and non-canonical effects. Thus, podocyte NLRP3 inflammasome activation is both sufficient and required for DKD and supports the concept that podocytes exert some immune cell-like functions. Hence, as podocyte NLRP3 exerts non-canonical and canonical effects, targeting NLRP3 may be a promising therapeutic approach in DKD.