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

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

doi:10.1042/cs20210865

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.

Highlights

Diabetic kidney disease (DKD) develops in up to 40% of diabetic patients and remains the major cause of end-stage renal disease worldwide contributing to increased morbidity and mortality with current therapies only slowing its progression at best [1]
The present study provides substantial evidence to indicate that one must be cautious in assuming a beneficial impact of NLRP3 inflammasome inhibitors on various organs as our results have failed to show a renoprotective effect of MCC950, while indicating potential adverse effects on the kidney in an established model of DKD
Diabetic animals treated with MCC950 were found to have enhanced mesangial expansion and increased glomerulosclerosis as compared with vehicle-treated diabetic animals

Summary

Introduction

Diabetic kidney disease (DKD) develops in up to 40% of diabetic patients and remains the major cause of end-stage renal disease worldwide contributing to increased morbidity and mortality with current therapies only slowing its progression at best [1]. It is of interest that increasing evidence supports the concept that nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome activation contributes to acute and chronic kidney disease including DKD [2,3,4,5]. With the wider application of strategies targeting the inflammasome axis, it is critical to define the renal impact of such approaches in order to avoid deleterious effects which could be a major obstacle for using such agents in certain clinical settings

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