The Role of the NLRP3 Inflammasome in Mediating Glomerular and Tubular Injury in Diabetic Nephropathy

Abstract

The NOD-like receptor protein 3 (NLRP3) inflammasome is a multi-protein signalling complex integral to the chronic inflammatory response, activated in response to sterile and non-sterile cellular damage. The assembly and activation of the NLRP3 inflammasome comprise a two-step process involving nuclear factor kappa B (NFkB)-mediated priming, followed by canonical, non-canonical or alternative signalling pathways. These result in the maturation and release of inflammatory cytokines interleukin 1 beta (IL1ß) and interleukin-18 (IL18), which are associated with chronic inflammatory conditions including diabetic kidney disease. Diabetic nephropathy is a condition affecting ∼40% of people with diabetes, the key underlying pathology of which is tubulointerstitial inflammation and fibrosis. There is growing evidence to suggest the involvement of the NLRP3 inflammasome in this chronic inflammation. Early deterioration of kidney function begins in the glomerulus, with tubular inflammation dictating the progression of late-stage disease. Priming and activation of the NLRP3 inflammasome have been linked to several clinical markers of nephropathy including proteinuria and albuminuria, in addition to morphological changes including mesangial expansion. Treatment options for diabetic nephropathy are limited, and research that examines the impact of directly targeting the NLRP3 inflammasome, or associated downstream components are beginning to gain favour, with several agents currently in clinical trials. This review will explore a role for NLRP3 inflammasome activation and signalling in mediating inflammation in diabetic nephropathy, specifically in the glomerulus and proximal tubule, before briefly describing the current position of therapeutic research in this field.

(+)-Catechin ameliorates diabetic nephropathy injury by inhibiting endoplasmic reticulum stress-related NLRP3-mediated inflammation

“…Previous studies have shown that the NLRP3 inflammasome is a key mediator of sterile inflammation during DN. 11,16 To further examine the molecular mechanisms by which (+)-catechin affects DN, proteins related to of NLRP3-associated inflammation were investigated. As shown in Fig.…”

“…Importantly, chronic low-grade sterile inflammation induced by proinflammatory cytokines is critical to the impairment of renal function in DN and can be triggered by NLRP3 inflammasome activation. 8,11,47 Thus, targeting the NLRP3 inflammasome may be a promising therapeutic strategy for DN. In this study, we observed the activation of NLRP3 in DN mice because NLRP3 protein and mRNA expression were upregulated in DN mice compared with normal mice.…”

“…8,9 Previous reports have shown that proximal tubular injury exacerbates the development and progression of DN, as indicated by the loss of renal function and increased levels of Scr, blood urea nitrogen (BUN), and albuminuria. [10][11][12] Notably, ER stress can exacerbate tubular injury during DN. 13 Multiple factors, such as high glucose, free fatty acids and advanced glycation end products (AGEs), can cause the accumulation of unfolded or misfolded proteins in the ER and trigger the unfolded protein response (UPR), which is an ER stress response.…”

“…[16][17][18][19] The activation of NLRP3 can promote pro-caspase-1 self-cleavage and the secretion of interleukin 1β (IL-1β) and interleukin 18 (IL-18), leading to inflammation and even cell death. 11 (+)-Catechin has been shown to have many benefits for diabetic patients, such as improving insulin resistance, reducing oxidative stress, and ameliorating ER stress. 20 Previous studies revealed that (+)-catechin exerted beneficial effects on many chronic diseases, such as neurodegenerative disease, cancer, and nonalcoholic fatty liver disease.…”

“…16–19 The activation of NLRP3 can promote pro-caspase-1 self-cleavage and the secretion of interleukin 1β (IL-1β) and interleukin 18 (IL-18), leading to inflammation and even cell death. 11…”