Excessive activation of the alternative complement pathway in autosomal dominant polycystic kidney disease.

Abstract

OBJECTIVES:

The complement system is involved in many immune complex-mediated kidney diseases, yet its role in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) has not been examined in detail.

METHODS AND RESULTS:

Screening of the glycoproteome of urine samples from ADPKD patients revealed that levels of complement factor B (CFB), serpin peptidase inhibitor, complement component 1 inhibitor (SERPING1) and complement component 9 (C9) increased, whereas complement component 1, r subcomponent-like (C1RL), CD55 and CD59 levels decreased with disease progression. Immunostaining and Western blot analysis confirmed the enhanced expression of CFB and C9 in cystic kidneys from ADPKD patients. Immunostaining also showed that the expressions of CFB and C9 in renal biopsy tissues from patients with other types of chronic kidney disease were lower than in tissues from ADPKD patients. The effect of the complement inhibitor rosmarinic acid (RMA) was evaluated in Pkd1(-/-) mice and Han:SPRD Cy/+ rats. Compared with vehicle-treated Pkd1(-/-) animals, RMA-treated mice had significantly lower serum creatinine (-50%) and blood urea nitrogen (-78%) levels, two kidneys/body weight ratio (-60%) and renal cystic index (-60%). Similar results were found in Cy/+ rats. Lower numbers of Ki67-positive nuclei and inflammatory cells and reduced fibrosis were observed in both animal models upon treatment with RMA.

CONCLUSIONS:

These results suggest that excessive activation of the alternative complement pathway is associated with ADPKD progression, probably mediated by cyst-lining epithelial cell proliferation, tubulointerstitial inflammatory cell infiltration and fibrosis. Targeting the complement system might represent a new therapeutic strategy for ADPKD.

• Authors: Z Su, X Wang, X Gao, Y Liu, C Pan, H Hu, R P Beyer, M Shi, J Zhou, J Zhang, A L Serra, R P Wüthrich, C Mei
• Journal: Journal of internal medicine (J Intern Med) Vol. 276 Issue 5 Pg. 470-85 (Nov 2014) ISSN: 1365-2796 [Electronic] England
• PMID: 24494798 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Association for the Publication of the Journal of Internal Medicine.

Chemical References

• Complement C3
• Complement C4
• Complement C9
• Complement System Proteins
• Complement Factor B

Topics

• Adult
• Animals
• Cell Proliferation
• Complement C3 (metabolism)
• Complement C4 (metabolism)
• Complement C9 (metabolism)
• Complement Factor B (metabolism)
• Complement Pathway, Alternative (drug effects)
• Complement System Proteins (urine)
• Disease Progression
• Epithelial Cells (metabolism)
• Fibrosis
• Humans
• Kidney (metabolism, pathology)
• Mice, Knockout
• Middle Aged
• Polycystic Kidney, Autosomal Dominant (immunology, pathology, urine)
• Rats