Adverse renal effects of NLRP3 inflammasome inhibition by MCC950 in an interventional model of diabetic kidney disease

Jakob A. Østergaard, Jay C. Jha, Arpeeta Sharma, Aozhi Dai, Judy S.Y. Choi, Judy B. De Haan, Mark E. Cooper, Karin Jandeleit-Dah*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

3 Citations (Scopus)
12 Downloads (Pure)

Abstract

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.

Original languageEnglish
JournalClinical Science
Volume136
Issue2
Pages (from-to)167-180
Number of pages14
ISSN0143-5221
DOIs
Publication statusPublished - Jan 2022

Keywords

  • Animals
  • Diabetes Mellitus, Experimental
  • Diabetic Nephropathies/pathology
  • Fibrosis
  • Furans/adverse effects
  • Indenes/adverse effects
  • Inflammasomes/drug effects
  • Inflammation/drug therapy
  • Male
  • Mice, Knockout, ApoE
  • NLR Family, Pyrin Domain-Containing 3 Protein/drug effects
  • Oxidative Stress/drug effects
  • Sulfonamides/adverse effects

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