<p>A small molecule inhibitor MCC950 ameliorates kidney injury in diabetic nephropathy by inhibiting NLRP3 inflammasome activation</p>

Abstract

Background Diabetic nephropathy (DN) is a lethal diabetic microvascular complication characterized by chronic low-grade inflammation. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is implicated in the progression of DN. MCC950 is a selective and potent inhibitor of NLRP3; however, its efficacy in DN requires further investigation. Methods To investigate the efficacy of MCC950 in DN, eight-week-old type 2 diabetic db/db mice received injections of MCC950 intraperitoneally (10 mg/kg) twice per week for 12 weeks. Urinary albumin-to-creatinine ratio (ACR) and neutrophil gelatinase-associated lipocalin (NGAL), renal function, pathological changes, markers of podocyte and fibrosis and NLPR3/caspase-1/IL-1β expression in the renal cortices of db/db mice were evaluated. High-glucose (HG)-treated rat glomerular mesangial cells were treated with various concentrations of MCC950 for 48 hrs. Markers of fibrosis and NLPR3/caspase-1/IL-1β expression in the glomerular mesangial cells were measured. Results The NLRP3 inflammasome was activated in db/db mice and HG-induced mesangial cells by upregulating NLRP3/caspase-1/IL-1β pathway. Inhibition of the NLRP3 inflammasome with MCC950 reduced the production of active caspase-1 and active IL-1β in db/db mice and HG-induced mesangial cells. MCC950 reduced serum creatinine, urinary ACR and NGAL, attenuated mesangial expansion with increased matrix and tubular dilatation, alleviated thickened glomerular basement membrane (GBM) and foot process fusion without affecting body weight and blood glucose levels in db/db mice. MCC950 increased the expression of podocin in db/db mice, and decreased the expression of TGF-β1, fibronectin, collagen I and α-smooth muscle actin (α-SMA) in renal cortices of db/db mice and HG-induced mesangial cells. Conclusion MCC950 ameliorated renal function, thickened GBM, podocyte injury and renal fibrosis in db/db mice, and decreased the production of fibrosis markers in HG-induced mesangial cells. MCC950 effectively ameliorated diabetic kidney injury by inhibiting NLRP3/caspase-1/IL-1β pathway, which may be a potential therapeutic strategy to prevent the progression of DN.

<p>Caspase-3 Promotes Diabetic Kidney Disease Through Gasdermin E-Mediated Progression to Secondary Necrosis During Apoptosis</p>

“…18 Chronic sterile inflammation has been proved to be the crucial basis for the progression of DKD. [19][20][21] Our previous study also demonstrated the participation of pyroptosis in diabetic tubular cells. 22 However, whether apoptosis could be an effective treatment target remained controversial hitherto.…”

Uncovering the Mechanism of Astragalus membranaceus in the Treatment of Diabetic Nephropathy Based on Network Pharmacology

“…At present, the incidence of DN is increasing year by year, which seriously threatens the prognosis and quality of life in diabetic patients [25]. The occurrence and development of DN are related to the disorder of glucose and lipid metabolism, oxidative stress, inflammatory reaction, and abnormal vasoactive substances [26,27]. In this study, the TCM-active ingredient-target network showed that the main active ingredient of AM quercetin, 7-O-methylisomucronulatol, formononetin, and isorhamnetin plays an important role in the network, indicating that they have potential research value in the treatment of DN.…”

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

“…In the diabetic apolipoprotein E knockout (apoE-/-) mice, administration of PPAR-γ agonist pioglitazone downregulated the expression of AGEs, RAGE, and NF-κB, and also diminished NLRP3, caspase-1, IL-18, and IL-1β levels [228]. MCC950, a selective inhibitor of NLRP3 andM920, a broad specificity caspase inhibitor, improved renal function, GBM thickening, podocyte injury, renal fibrosis, and NLRP3-dependent markers in db/db mice [229,230].…”