The NLRP3 Inflammasome Promotes Renal Inflammation and... : Journal of the American Society of Nephrology (original) (raw)

Basic Research

Vilaysane, Akosua*; Chun, Justin*; Seamone, Mark E.*,‡; Wang, Wenjie*; Chin, Rick*; Hirota, Simon*; Li, Yan*; Clark, Sharon A.*; Tschopp, Jurg†; Trpkov, Kiril‡; Hemmelgarn, Brenda R.*; Beck, Paul L.*; Muruve, Daniel A.*

Departments of *Medicine and

‡Pathology, University of Calgary, Calgary, Alberta, Canada; and

†Department of Biochemistry, University of Lausanne, Epalinges, Switzerland

Correspondence: Dr. Daniel A. Muruve, Department of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1 Canada. Phone: 403-220-2418; Fax: 403-210-3949; E-mail: [email protected]

Received February 3, 2010

Accepted May 25, 2010

Abstract

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.