GPR108 deficiency promotes urate-induced renal interstitial fibrosis

Area of Science:

• Nephrology
• Molecular Biology
• Immunology

Background:

• Chronic hyperuricemia from purine metabolism contributes to kidney injury, including inflammation and fibrosis.
• Epithelial-mesenchymal transition (EMT) is a key process in renal fibrosis.
• G protein-coupled receptor 108 (GPR108) is a known negative regulator of inflammation, but its role in kidney disease is unknown.

Purpose of the Study:

• To investigate the role of GPR108 in hyperuricemia-induced chronic kidney disease (CKD).
• To explore GPR108's impact on renal fibrosis, inflammation, and EMT.

Main Methods:

• Utilized adenine-fed mice to model hyperuricemia-induced nephropathy.
• Employed in vitro studies using primary cultured renal tubular epithelial cells from Gpr108 knockout mice.
• Assessed renal fibrosis, EMT markers, cytokine levels, TGF-β1, and NF-κB activation.

Main Results:

• Gpr108-deficient mice showed exacerbated renal fibrosis, EMT, and increased cytokine levels.
• Primary renal tubular epithelial cells lacking GPR108 exhibited heightened sensitivity to uric acid-induced EMT.
• Uric acid exposure in Gpr108-deficient cells led to increased TGF-β1 production and NF-κB activation.

Conclusions:

• GPR108 deficiency exacerbates renal inflammation and fibrosis in hyperuricemia-induced CKD.
• GPR108 acts as a protective modulator by inhibiting NF-κB-driven EMT and TGF-β1 signaling.
• GPR108 presents a potential therapeutic target for mitigating renal interstitial fibrosis in CKD.