期刊
JOURNAL OF INTERNAL MEDICINE
卷 276, 期 5, 页码 470-485出版社
WILEY
DOI: 10.1111/joim.12214
关键词
autosomal dominant polycystic kidney disease; complement; complement inhibitor; glycoproteomics; urine
资金
- National High Technology Research and Development Program 863 Project [2007AA02Z3Z1]
- National Natural Science Foundation of China General Projects [30971368, 30871179]
- Shanghai Key Discipline Project [B902]
- Major National Science and Technology Project [2009ZX09102]
- Shanghai Science and Technology Commission Major Research Project [11431920800]
- Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents
- Qianjiang Talents Project of Science and Technology Department in Zhejiang Province
- Shanghai International Science and Technology Cooperation Fund Project [0954070200]
- Shanghai Science and Technology Committee General Project [09ZR1410400]
- National Institute of Child Health and Human Development [P30 HD02274]
- Swiss National Science Foundation [320030-144093, 310030-132597]
- Swiss National Science Foundation (SNF) [310030_132597, 320030_144093] Funding Source: Swiss National Science Foundation (SNF)
ObjectivesThe 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 ResultsScreening 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. ConclusionsThese 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.
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