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Reduced decay-accelerating factor expression promotes complement-mediated cystogenesis in murine ADPKD
Sofia Bin1,2,3, Miran Yoo4, Paolo Molinari1
1Translational Transplant Research Center and Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Insights
Loss of Pkd1 in autosomal dominant polycystic kidney disease (ADPKD) promotes complement activation, driving cyst growth. Inhibiting C5aR1 offers a potential therapeutic target for ADPKD.
Area of Science:
- Nephrology
- Immunology
- Genetics
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder caused by mutations in PKD1 or PKD2.
- Patients exhibit complement activation in renal fluids, but its role in cyst development is unknown.
- PKD1 deficiency is linked to altered complement gene expression and reduced complement regulators.
Purpose of the Study:
- To investigate the causal link between complement activation and cyst growth in ADPKD.
- To explore the role of complement component 3 (C3) and its receptors in ADPKD pathogenesis.
- To identify potential therapeutic targets for ADPKD by examining complement pathways.
Main Methods:
- Utilized a Pkd1-deficient (Pkd1KO) renal tubular cell line.
- Generated conditional Pkd1-/- C3-/- mice and Pkd1-/- C3+/+ controls.
- Assessed gene and protein expression of complement factors and regulators; evaluated cystogenesis, renal function, and inflammation.
Main Results:
- Pkd1-deficient cells showed increased complement gene expression (C3, C5, C3aR, C5aR1) and decreased complement regulators (DAF, CD59, Crry).
- Pkd1-/- C3-/- mice exhibited reduced cystogenesis, preserved kidney function, and less inflammation compared to controls.
- Restoring Pkd1 function or inhibiting C5aR1 significantly reduced cell proliferation in Pkd1KO cells.
Conclusions:
- Loss of Pkd1 in renal tubular cells leads to uncontrolled complement activation via downregulation of DAF.
- Enhanced C5a formation and C5aR1 activation promote ADPKD cyst growth.
- C5aR1 represents a promising therapeutic target for managing ADPKD.
Abstract:
Patients with autosomal dominant polycystic kidney disease (ADPKD), a genetic disease due to mutations of the PKD1 or PKD2 gene, show signs of complement activation in the urine and cystic fluid, but their pathogenic role in cystogenesis is unclear. We tested the causal relationship between complement activation and cyst growth using a Pkd1KO renal tubular cell line and newly generated conditional Pkd1-/- C3-/- mice. Pkd1-deficient tubular cells have increased expression of complement-related genes (C3, C5, CfB, C3ar, and C5ar1), while the gene and protein expression of complement regulators DAF, CD59, and Crry is decreased. Pkd1-/- C3-/- mice are unable to fully activate the complement cascade and are characterized by a significantly slower kidney cystogenesis, preserved renal function, and reduced intrarenal inflammation compared with Pkd1-/- C3+/+ controls. Transgenic expression of the cytoplasmic C-terminal tail of Pkd1 in Pkd1KO cells lowered C5ar1 expression, restored Daf levels, and reduced cell proliferation. Consistently, both DAF overexpression and pharmacological inhibition of C5aR1 (but not C3aR) reduced Pkd1KO cell proliferation. In conclusion, the loss of Pkd1 promotes unleashed activation of locally produced complement by downregulating DAF expression in renal tubular cells. Increased C5a formation and C5aR1 activation in tubular cells promotes cyst growth, offering a new therapeutic target.
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