.png){kind=icon}
.png){kind=icon}
Return
Succinate promotes renal inflammation and fibrosis by activating the NLRP3 inflammasome in macrophages via GPR91 signaling
.png){kind=icon}
OA
AI
Y
J
X
X
S
J
Y
Q
Y
L
S
Q
J
L
Z
DOI：10.1186/s10020-026-01585-3.png)
.png){kind=icon}
Original request for help.png){kind=icon}
Share.png){kind=icon}
Save
Abstract
En 中文
Aberrant succinate accumulation functions as a potent metabolic danger signal in various inflammatory diseases. However, the specific contribution of the succinate-GPR91 signaling axis to the pathogenesis of renal fibrosis remains incompletely defined. Succinate levels were analyzed in kidney tissues from patients with obstructive nephropathy and mice with unilateral ureteral obstruction (UUO). The impact of succinate on renal fibrosis was evaluated using exogenous succinate administration and pharmacological inhibition with dimethyl malonate (DMM). Mechanistic studies employed Gpr91-knockout mice, NLRP3-knockout mice, and cultured macrophages to dissect the downstream signaling pathways linking metabolic alterations to innate immunity. We observed significantly elevated succinate levels in fibrotic kidneys from both patients and UUO mice, which correlated positively with disease severity. Functionally, exogenous succinate markedly exacerbated renal inflammation and fibrosis, whereas pharmacological inhibition with DMM attenuated these pathological changes. Mechanistically, we demonstrated that succinate mainly activates its receptor GPR91 on macrophages to trigger NLRP3 inflammasome assembly and IL-1β secretion, a pro-fibrotic cascade effectively abolished by genetic ablation of Gpr91 or NLRP3 in vivo, or by their pharmacological blockade in vitro. This study establishes the succinate-GPR91 axis as a pivotal metabolic driver of renal fibrosis, likely primarily through macrophage-mediated NLRP3 inflammasome activation. Targeting this pathway represents a promising therapeutic strategy for interfering with the progression of chronic kidney disease.
Keywords:
Renal fibrosis
Succinate
GPR91
NLRP3 inflammasome
Macrophage
Journal
IF:
6.4
Papers:
3.2K
Citations:
8.3K
Organization
Cited Papers