Adverse renal effects of NLRP3 inflammasome inhibition by MCC950 in an interventional model of diabetic kidney disease
| Autor: | Jakob A. Østergaard, Jay C. Jha, Arpeeta Sharma, Aozhi Dai, Judy S.Y. Choi, Judy B. de Haan, Mark E. Cooper, Karin Jandeleit-Dahm |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Male
Inflammasomes Mice Knockout ApoE Oxidative Stress/drug effects Diabetes Mellitus Experimental Furans/adverse effects Indenes/adverse effects Inflammation/drug therapy NLR Family Pyrin Domain-Containing 3 Protein Animals Diabetic Nephropathies MCC950 Furans Research Articles Diabetes & Metabolic Disorders Inflammation Diabetic Nephropathies/pathology Sulfonamides diabetic nephropathy Inflammasomes/drug effects Sulfonamides/adverse effects General Medicine Fibrosis NLRP3 inflammasome Oxidative Stress Indenes NLR Family Pyrin Domain-Containing 3 Protein/drug effects |
| Zdroj: | Østergaard, J A, Jha, J C, Sharma, A, Dai, A, Choi, J S Y, De Haan, J B, Cooper, M E & Jandeleit-Dah, K 2022, ' Adverse renal effects of NLRP3 inflammasome inhibition by MCC950 in an interventional model of diabetic kidney disease ', Clinical Science, vol. 136, no. 2, pp. 167-180 . https://doi.org/10.1042/CS20210865 Clinical Science (London, England : 1979) |
| ISSN: | 1470-8736 0143-5221 |
| Popis: | Activation of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome has been reported in diabetic complications including diabetic kidney disease (DKD). However, it remains unknown if NLRP3 inhibition is renoprotective in a clinically relevant interventional approach with established DKD. We therefore examined the effect of the NLRP3-specific inhibitor MCC950 in streptozotocin-induced diabetic mice to measure the impact of NLRP3 inhibition on renal inflammation and associated pathology in DKD. We identified an adverse effect of MCC950 on renal pathology in diabetic animals. Indeed, MCC950-treated diabetic animals showed increased renal inflammation and macrophage infiltration in association with enhanced oxidative stress as well as increased mesangial expansion and glomerulosclerosis when compared with vehicle-treated diabetic animals. Inhibition of the inflammasome by MCC950 in diabetic mice led to renal up-regulation of markers of inflammation (Il1β, Il18 and Mcp1), fibrosis (Col1, Col4, Fn1, α-SMA, Ctgf and Tgfβ1) and oxidative stress (Nox2, Nox4 and nitrotyrosine). In addition, enhanced glomerular accumulation of pro-inflammatory CD68 positive cells and pro-oxidant factor nitrotyrosine was identified in the MCC950-treated diabetic compared with vehicle-treated diabetic animals. Collectively, in this interventional model of established DKD, NLRP3 inhibition with MCC950 did not show renoprotective effects in diabetic mice. On the contrary, diabetic mice treated with MCC950 exhibited adverse renal effects particularly enhanced renal inflammation and injury including mesangial expansion and glomerulosclerosis. |
| Databáze: | OpenAIRE |
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