Affiliation:
1. The NO. 981 Hospital of Chinese People's Liberation Army
2. Beidaihe Rehabilitation and Recuperation Center of the Chinese People's Liberation Army
3. Kidney Institution of the Chinese People's Liberation Army, Chang Zheng Hospital, the Navy Military Medical University
4. Hainan Hospital of General Hospital of Chinese People's Liberation Army
5. TongJi University
6. Shanghai University of Traditional Chinese Medicine
Abstract
Abstract
C5b-9 complex, the final product of complement, is overproduced during cystogenesis in the kidneys of rapid-onset mice with Pkd1 gene deficiency at postnatal day (PD)10. Compared with rapid-onset polycystic kidney disease (PKD) model, cyst enlargement is much less progressive in mice when Pkd1 gene inactivation at PD30 (chronic-onset model); however, C5b-9 infusion significantly accelerated ADPKD progression in this model. These histological data provide evidence that C5b-9 triggers renal cell apoptosis in the middle stage (PD180) and promotes cell proliferation in the late stage (PD240) in PKD mice. However, in vitro C5b-9 neither stimulated renal tubular epithelial cell (RTEC) apoptosis nor promoted RTEC proliferation, indicating that the C5b-9 indirectly affects RTECs. Furthermore, our results demonstrate that the impact of C5b-9 on cyst enlargement is significantly weakened when macrophages are depleted with liposomal clodronate (LC), suggesting that macrophages play a key role in the development of ADPKD. Moreover, C5b-9 drives bone-marrow-derived macrophages (BMDMs) to highly express TNF-α in vitro, resulting in increased cell apoptosis and contributing to cystogenesis. Additionally, the macrophages underwent M1-to-M2 transition and secreted high levels of IL-10, when cocultured with RTECs. IL-10, an M2-specific cytokine marker, remarkably stimulated RTEC proliferation. After LC-induced macrophage depletion, infusion of C5b-9-activated BMDMs significantly increased cystic phenotype in mice, proving that macrophages are vital for C5b-9-induced ADPKD.
Publisher
Research Square Platform LLC