The NLRP3 Inflammasome Promotes Renal Inflammation and Contributes to CKD

TLDR

Inflammation drives chronic kidney disease progression, and inflammasome‑derived cytokines IL‑1β and IL‑18 are implicated, yet their regulation during renal injury remains unclear. We demonstrated that unilateral ureteral obstruction activates the NLRP3 inflammasome, with caspase‑1, IL‑1β, and IL‑18 processing, and that NLRP3 mediates injury and inflammation in both hematopoietic and non‑hematopoietic cells as shown by bone‑marrow chimera experiments. NLRP3 deficiency in mice reduced tubular injury, inflammation, fibrosis, caspase‑1 activation, and cytokine maturation after UUO, while human renal biopsies revealed elevated NLRP3 mRNA correlating with impaired renal function, confirming NLRP3 as a therapeutic target in progressive CKD.

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.