Glomerular mesangial cells derived complement factor H regulates complement activation, influences cell proliferation, and maintains actin cytoskeleton

Abstract

Complement factor H (CFH), mainly produced in the liver, is a key alternative complement pathway regulator. Recent studies unveiled some novel functions of CFH independent of complement activation. The kidney, as a vulnerable organ to complement-induced damage, produced several complement proteins. Here, we examined the functions of CFH in glomerular mesangial cells. Using single-cell sequencing data of the kidney, we identified glomerular mesangial cells as the kidney intrinsic cells expressing the highest amount of CFH. We then confirmed the expression of CFH in primary human glomerular mesangial cells (pHGMCs). Our findings revealed that exposure IgA1-containing immune complexes from IgA nephropathy patients led to a reduction in the relative mRNA expression of CFH in pHGMCs. Silencing CFH in pHGMCs led to increased deposition of C3c and C5b-9, especially after exposure to IgAN-IgA1-ICs, while overexpression of CFH reduced the deposition. Furthermore, pHGMCs-derived CFH was more efficient in regulating complement activation than exogenously supplemented CFH. In addition to its canonical function, we also discovered that pHGMCs-derived CFH downregulated KLF4 and p21 and up-regulated CDK 2/4/6, cyclin D1/E2, thereby promoting cell proliferation. Moreover, altering CFH expression in pHGMCs affected the expression of Cdc42, as well as actin cytoskeleton and cell motility. However, exogenously supplemented CFH did not influence cell proliferation and the cytoskeleton of pHGMCs. Our results indicate that CFH derived from glomerular mesangial cells not only plays a canonical regulatory role in complement activation but also has non-canonical functions, such as affecting cell proliferation and maintaining the actin cytoskeleton.

Keywords: Cell cycle; Complement activation; Complement factor H; Cytoskeleton; Mesangial cell.