Possible role of complement factor H in podocytes in clearing glomerular subendothelial immune complex deposits

Takeshi Zoshima,Satoshi Hara,Michio Nagata,Ira Pastan,Masakazu Yamagishi,Mitsuhiro Kawano,Taiji Matsusaka

doi:10.1038/s41598-019-44380-3

Abstract

Podocytes are known to express various complement factors including complement factor H (CFH) and to promote the removal of both subendothelial and subepithelial immune complex (IC) deposits. Using podocyte-selective injury model NEP25 mice and an IgG3-producing hybridoma clone 2B11.3 established by MRL/lpr mice, the present study investigated the role of podocyte complement regulation in only subendothelial IC deposition. In immunotoxin (LMB2) induced fatal podocyte injury (NEP25/LMB2) at day 12, glomerular CFH and C3a receptor (C3aR) expression was decreased as compared with NEP25/vehicle mice. In contrast, in sublytic podocyte injury 5 days after LMB2, glomerular CFH and C3aR expression was increased as compared with NEP25/vehicle mice. Intra-abdominal injection of 2B11.3 hybridoma to NEP25 mice (NEP25/hybridoma) caused IC deposition limited to the subendothelial area associated with unaltered CFH expression. NEP25/hybridoma mice with sublytic podocyte injury (NEP25/hybridoma/LMB2) resulted in increased glomerular CFH expression (1.7-fold) accompanied by decreased subendothelial IC deposition, as compared with NEP25/hybridoma. Immunostaining revealed that CFH was dominantly expressed in podocytes of NEP25/hybridoma/LMB2. In addition, puromycin-induced sublytic podocyte injury promoted CFH expression in immortalized mouse podocytes in vitro. These results suggest that in response to sublytic levels of injury, podocyte induced CFH expression locally and clearance of subendothelial IC deposits.

Highlights

Glomerular immune complex (IC) deposition initiates glomerulonephritis via complement pathway activation and chemotaxis of inflammatory infiltrates[1]
As previously reported[12], LMB2-treated NEP25 mice (NEP25/LMB2) at 12 days showed glomerular tuft collapse with epithelial cell hyperplasia accompanied by extensive podocyte loss, resembling collapsing focal segmental glomerulosclerosis (FSGS) (Fig. 1a)
The present study focused on the role of intrinsic glomerular cell-derived complement factors as a local processor of subendothelial IC deposition

Summary

Introduction

Glomerular immune complex (IC) deposition initiates glomerulonephritis via complement pathway activation and chemotaxis of inflammatory infiltrates[1]. Www.nature.com/scientificreports the clearance of ICs. Complement factor H (CFH), a representative complement regulatory component, acts as CR1 on rodent platelets[4], and systemic CFH depletion has been shown to increase glomerular ICs in rodent IC-mediated glomerulonephritis models[5]. Complement factor H (CFH), a representative complement regulatory component, acts as CR1 on rodent platelets[4], and systemic CFH depletion has been shown to increase glomerular ICs in rodent IC-mediated glomerulonephritis models[5] In this way, complement regulatory factors are one of the key players in the degradation of IC deposition. In the mouse model of IC-mediated glomerulonephritis induced by chronic serum sickness (CSS), podocytes expressed CFH and facilitated the removal of glomerular ICs in both the subepithelial and subendothelial areas, and seemed to be the functional surrogate for human CR110. This uncertainty prompted us to investigate the impact of sublytic podocyte injury on the regulation of subendothelial IC deposition

Methods

Results

Conclusion