The NLRP3 inflammasome promotes renal inflammation and contributes to CKD.
Inflammation significantly contributes to the progression of chronic kidney disease (CKD). Inflammasome-dependent cytokines, such as IL-1β and IL-18, play a role in CKD, but their regulation during renal injury is unknown. Here, we analyzed the processing of caspase-1, IL-1β, and IL-18 after unilateral ureteral obstruction (UUO) in mice, which suggested activation of the Nlrp3 inflammasome during renal injury. Compared with wild-type mice, Nlrp3(-/-) mice had less tubular injury, inflammation, and fibrosis after UUO, associated with a reduction in caspase-1 activation and maturation of IL-1β and IL-18; these data confirm that the Nlrp3 inflammasome upregulates these cytokines in the kidney during injury. Bone marrow chimeras revealed that Nlrp3 mediates the injurious/inflammatory processes in both hematopoietic and nonhematopoietic cellular compartments. In tissue from human renal biopsies, a wide variety of nondiabetic kidney diseases exhibited increased expression of NLRP3 mRNA, which correlated with renal function. Taken together, these results strongly support a role for NLRP3 in renal injury and identify the inflammasome as a possible therapeutic target in the treatment of patients with progressive CKD.
Vilaysane
Akosua
A
Department of Medicine, University of Calgary, Calgary, Alberta, Canada.
Chun
Justin
J
Seamone
Mark E
ME
Wang
Wenjie
W
Chin
Rick
R
Hirota
Simon
S
Li
Yan
Y
Clark
Sharon A
SA
Tschopp
Jurg
J
Trpkov
Kiril
K
Hemmelgarn
Brenda R
BR
Beck
Paul L
PL
Muruve
Daniel A
DA
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005355:Fibrosis; D006801:Humans; D007668:Kidney / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009393:Nephritis / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000378:metabolism*; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology
D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D012333:RNA, Messenger