The role of complement C3 in focal inflammation and development of kidney cysts induced by Pkd1 inactivation (690.3)

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common life‐threatening genetic diseases and is characterized by early formation and gradual enlargement of multiple kidney cysts, which eventually results in end‐stage renal disease (ESRD). Mutations in PKD1 (polycystin‐1, PC1) or PKD2 (polycystin‐2, PC2) account for 85% and 15% of this disease respectively. PC1 is a large integral membrane protein with multiple functions. However, the mechanism for development of multiple kidney cysts induced by PKD1 mutation is not fully understood. In order to find important proteins in renal cystic fluid from ADPKD mice induced by Pkd1 inactivation, we did mass spectral analysis. Our results showed that complement C3 and its cleaved products are the most abundant protein in the cystic fluid, which was further confirmed by Western blots in kidney tissue from ADPKD mice and ADPKD patients. Furthermore, we found C3 and its cleaved fragments are significant increased around kidney cysts epithelium line by immunostaining, and its distribution is consistant with focal fibrosis. As reported previously, the expansion of kidney cysts is a slow inflammation and fibrosis process. Our finding indicates that C3 and its cleaved products may play critical role for this process. Inhibition of focal C3 and its cleavage could be a unique regimen for ADPKD treatment.