STING Promotes the Progression of ADPKD by Regulating Mitochondrial Function, Inflammation, Fibrosis, and Apoptosis

Area of Science:

• Genetics
• Immunology
• Nephrology

Background:

• Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder characterized by kidney cyst formation.
• DNA damage in cystic cells is a hallmark of ADPKD, but the underlying mechanisms are not fully understood.
• The STING (stimulator of interferon genes) pathway detects cytosolic DNA and initiates inflammatory responses, yet its role in ADPKD is unclear.

Purpose of the Study:

• To investigate the role and mechanisms of the STING pathway in ADPKD.
• To determine if targeting the STING pathway can ameliorate ADPKD phenotypes in mouse models.

Main Methods:

• Analysis of STING expression in Pkd1 mutant mouse kidneys.
• Assessment of STING activation by nuclear and mitochondrial DNA.
• Evaluation of STING inhibitor (C-176) efficacy in Pkd1 mutant mouse models.
• Examination of cellular and molecular changes including NF-κB activation, macrophage recruitment, mitochondrial function, micronuclei formation, cell death, and fibrosis.

Main Results:

• Pkd1 mutant kidneys exhibit upregulated STING, activated by nuclear and mitochondrial DNA.
• STING activation promotes cyst growth by activating NF-κB, upregulating TNF-α and MCP-1, and recruiting macrophages.
• STING inhibition with C-176 reduced cyst growth in two different Pkd1 mutant mouse models.
• STING targeting normalized mitochondrial function, reduced DNA damage markers (micronuclei), induced apoptosis via p53, and decreased renal fibrosis.

Conclusions:

• The STING pathway is upregulated and contributes to cystogenesis and progression in ADPKD.
• Targeting STING represents a promising therapeutic strategy for treating ADPKD.
• STING inhibition offers a multi-faceted approach by addressing inflammation, cell death, and fibrosis in ADPKD kidneys.