An NLRP3-specific inflammasome inhibitor attenuates crystal-induced kidney fibrosis in mice

Abstract

Intrarenal crystal formation activates the Nlrp3 inflammasome in myeloid cells and triggers a profound inflammatory response. Here, we studied whether a specific inhibitor of the Nlrp3 inflammasome, CP-456,773, can prevent kidney fibrosis in a murine model of crystal nephropathy induced by diets rich in oxalate or adenine. Inflammasome activation in renal dendritic cells and the resulting interleukin (IL)-1β and IL-18 production were markedly reduced by CP-456,773 treatment both ex vivo and in vivo. We directly visualized intrarenal inflammasome activation and its inhibition by CP-456,773 in vivo by adoptive transfer of bone marrow cells transduced with interleukin-1β-Gaussia luciferase, a proteolytic luciferase-based reporter for inflammasome activation, into irradiated mice. CP-456,773 treatment strongly attenuated kidney fibrosis when given early in the genesis of crystal nephropathy, but was unable to reverse established crystal-induced fibrosis. The urinary IL-18 concentration appeared to be a useful noninvasive biomarker for renal inflammasome activation. Finally, NLRP3 inhibition did not compromise adaptive immune responses as previously reported for the global inhibition of IL-1 signaling. Thus, early NLRP3 inhibition by CP-456,773 may be an effective treatment for crystal nephropathy. Use of iGLuc transfected cells introduces a novel imaging technique for inflammasome activation in mice.

Mitochondria-Targeted Antioxidant Mito-Tempo Protects Against Aldosterone-Induced Renal Injury In Vivo

“…In addition, Vilaysane et al showed that activation of the Nlrp3 inflammasome is involved in UUO-induced renal inflammation and leads to renal fibrosis [26]. Recently, it was also demonstrated that an Nlrp3-specific inflammasome inhibitor significantly improved crystal-induced renal inflammation and fibrosis [27]. We previously showed that mtROS-mediated Nlrp3 inflammasome activation directly contributed to Aldo-induced renal injury in vitro .…”

Novel Insights into Crystal-Induced Kidney Injury

“…Deficiency of inflammasome components, NLRP3, and ASC in mice reduced renal inflammation during progressive renal failure in nephrocal­cinosis-related CKD [39, 40]. Furthermore, chemical inhibition of NLRP3 using a specific inhibitor – CP-456773 or β-hydroxybutyrate – reduced renal inflammation and progressive decline in renal function in murine nephrocalcinosis-related CKD [40, 41]. Inflammasome activation leads to secretion of mature IL-1β and IL-18 that contribute to renal inflammation.…”

“…Inflammasome activation leads to secretion of mature IL-1β and IL-18 that contribute to renal inflammation. Surprisingly, IL-1 receptor inhibition using anakinra has no effect on progressive decline in renal function in murine nephrocalcinosis-related CKD [40, 41], suggesting a contribution of inflammasome-independent functions of NLRP3, which involve transforming growth factor beta receptor signaling-mediated renal fibrosis [42]. Indeed, chemical inhibition of NLRP3 by CP-456773 during oxalate and adenine nephropathy or by β-hydroxybutyrate during oxalate nephropathy reduced intrarenal fibrosis in murine crystalline CKD models [40, 41].…”

Inflammation in Nonimmune-Mediated Chronic Kidney Disease

“…In most of these studies, the amount of T-cells in the renal interstitium correlates positively with the progression of albuminuria, creatinine retention, and renal structural damage, as shown in Table 1 [36][37][38][39][40][41][42][43]. Corroborating these findings, a number of experimental studies showing significant evidence that anti-inflammatory treatment, as well as the knockout (KO) of specific pro-inflammatory genes can be effective to detain the evolution of nephropathy in different animal models of CKD, have been recently published, as shown in Table 2 [44][45][46][47][48][49][50][51][52].…”