Key result
FXR activation with GW4064 attenuates aldosterone-induced renal fibrosis and oxidative stress in mice.
Why the study?
Pharmacological activation of FXR as a modulator of aldosterone-induced renal fibrosis and pyroptosis-associated signaling in chronic kidney disease was unknown.
Does pharmacological activation of FXR with GW4064 attenuate aldosterone-induced renal fibrosis and pyroptosis-associated signaling in mice?
Does pharmacological activation of FXR with GW4064 attenuate aldosterone-induced renal fibrosis and pyroptosis-associated signaling in mice?
p-value: p=<0.001
Pharmacological activation of FXR using GW4064 attenuates aldosterone-induced renal injury, fibrosis, and oxidative stress in a preclinical model, highlighting its potential as a therapeutic target for chronic kidney disease.
Hypothesis-generating for FXR agonism in aldosterone-driven renal injury; leaves open clinical translation in CKD.
Background: Excessive aldosterone (ALD) is a major contributor to chronic kidney disease (CKD) as it promotes renal inflammation, oxidative stress, tubular injury, epithelial-mesenchymal transition (EMT), and fibrosis. The farnesoid X receptor (FXR) has emerged as a protective regulator in kidney disease; however, whether pharmacological activation of FXR modulates ALD-induced renal fibrosis and pyroptosis-associated signaling remains unknown. Methods: A mouse model of ALD-induced renal injury was established by continuous ALD infusion combined with a high-salt diet, with or without treatment with the FXR agonist, GW4064. Renal histopathology, fibrosis, renal function, oxidative stress, apoptosis, pyroptosis, and EMT-related markers were evaluated using histological staining, biochemical assays, immunohistochemistry, RT-qPCR, Western blotting, ELISA, and lactate dehydrogenase (LDH) assays. In vitro, ALD-treated HK-2 renal tubular epithelial cells were used to assess cell viability, reactive oxygen species (ROS) generation, apoptosis, oxidative stress, inflammatory cytokine release, and pyroptosis-related signaling. Results: FXR expression was significantly downregulated in the kidneys of ALD-infused mice and in ALD-treated HK-2 cells. Pharmacological activation of FXR with GW4064 reduced blood pressure, improved renal histopathology and function, and attenuated renal hypertrophy in mice infused with ALD. GW4064 markedly decreased collagen deposition, restored E-cadherin expression, and suppressed the expression of profibrotic and EMT-related markers. In HK-2 cells, FXR activation improved cell viability and reduced ROS accumulation, lipid peroxidation, apoptosis, LDH release, and interleukin-1 beta (IL-1β) and IL-18 secretion. Furthermore, GW4064 suppressed the expression of pyroptosis-related proteins, including NLR family pyrin domain-containing 3 (NLRP3), caspase 1, gasdermin D (GSDMD), and phosphorylated NF-κB. Conclusion: Pharmacological activation of FXR attenuates ALD-induced renal injury by reducing oxidative stress, apoptosis, inflammasome- and pyroptosis-associated signaling, EMT, and fibrosis. These findings suggest that FXR activation may represent a promising therapeutic strategy for CKD associated with ALD, although additional studies using genetic approaches and canonical pyroptosis markers are required to confirm the underlying mechanisms.
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Gu et al. (2026) studied Aldosterone-induced renal injury and fibrosis (n=24). GW4064 vs. Aldosterone + vehicle was evaluated on Renal fibrosis and tubular injury (preclinical endpoints) (p=<0.001). Pharmacological activation of FXR with GW4064 significantly attenuated aldosterone-induced renal fibrosis, oxidative stress, apoptosis, and inflammasome-associated pyroptotic signaling in mice.
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