NLRP3-mediated pyroptosis in diabetic nephropathy

Abstract

Diabetic nephropathy (DN) is the main cause of end-stage renal disease (ESRD), which is characterized by a series of abnormal changes such as glomerulosclerosis, podocyte loss, renal tubular atrophy and excessive deposition of extracellular matrix. Simultaneously, the occurrence of inflammatory reaction can promote the aggravation of DN-induced kidney injury. The most important processes in the canonical inflammasome pathway are inflammasome activation and membrane pore formation mediated by gasdermin family. Converging studies shows that pyroptosis can occur in renal intrinsic cells and participate in the development of DN, and its activation mechanism involves a variety of signaling pathways. Meanwhile, the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome can not only lead to the occurrence of inflammatory response, but also induce pyroptosis. In addition, a number of drugs targeting pyroptosis-associated proteins have been shown to have potential for treating DN. Consequently, the pathogenesis of pyroptosis and several possible activation pathways of NLRP3 inflammasome were reviewed, and the potential drugs used to treat pyroptosis in DN were summarized in this review. Although relevant studies are still not thorough and comprehensive, these findings still have certain reference value for the understanding, treatment and prognosis of DN.

Integrated multiple-microarray analysis and mendelian randomization to identify novel targets involved in diabetic nephropathy

“…( 42 ) revealed that the toll-like receptor 4/nuclear transcription factor κB signaling pathway could induce GSDMD-mediated pyroptosis in tubular cells in DN. Meanwhile, the activation of the NOD-like receptor thermal protein domain associated protein 3 could also induce pyroptosis in DN ( 43 ). In addition, several drugs targeting pyroptosis-associated proteins have been shown to have the potential to treat DN ( 44 – 46 ).…”

Hirudin in the Treatment of Chronic Kidney Disease

“…Gasdermin D (Gsdmd) is a key factor in lytic and highly inflammatory forms of pyroptosis, and acts as a specific substrate for inflammatory caspases [ 92 ]. Converging studies reveal that pyroptosis can occur in renal intrinsic cells, and is involved in the development of DN [ 93 ]. A study found that hirudin effectively ameliorated kidney injury in DN mice by targeting Gsdmd; hirudin also suppressed pyroptosis in primary GECs, RTECs, and bone-marrow-derived macrophages in vitro [ 75 ].…”

Exploring exercise-driven inhibition of pyroptosis: novel insights into treating diabetes mellitus and its complications

“…In a streptozotocin (STZ)-induced DN rat model, ASC and caspase-1 levels were observed to increase, along with hyperuricemia and hyperlipidemia with higher proinflammatory factors levels ( 60 ). The implication of NLRP3 inflammasome activation in DN is noteworthy, as the overexpression of NLRP3 inflammasome can lead to pyroptosis ( 60 , 61 ). Further research has documented that suppression of NLRP3 inflammasome activation alleviates renal injury in DN.…”