Clusterin Deficiency Predisposes C57BL/6j Mice to Cationic Bovine Serum Albumin-Induced Glomerular Inflammation

Pengcheng Sun; Shijian Feng; Qiunong Guan; Hans Adomat; Sean Barbour; Martin E Gleave; Christopher Y C Nguan; Wanhai Xu; Caigan Du

doi:10.2147/JIR.S285985

Clusterin Deficiency Predisposes C57BL/6j Mice to Cationic Bovine Serum Albumin-Induced Glomerular Inflammation

J Inflamm Res. 2020 Nov 24:13:969-983. doi: 10.2147/JIR.S285985. eCollection 2020.

Authors

Pengcheng Sun^{1

2}, Shijian Feng^{1

3}, Qiunong Guan¹, Hans Adomat¹, Sean Barbour⁴, Martin E Gleave¹, Christopher Y C Nguan¹, Wanhai Xu⁵, Caigan Du¹

Affiliations

¹ Department of Urologic Sciences, University of British Columbia, Vancouver, BC V6H 3Z6, Canada.
² Department of Gynecology and Obstetrics, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, People's Republic of China.
³ Department of Urology, Institute of Reconstructive Urology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People's Republic of China.
⁴ Division of Nephrology, Department of Medicine, University of British Columbia, Vancouver, BC V5T 3A5, Canada.
⁵ Heilongjiang Key Laboratory of Scientific Research in Urology, Department of Urology, The Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, People's Republic of China.

Abstract

Background: Membranous nephropathy (MN) is a specific entity of glomerulonephritis, and its glomerular inflammation is characterized by the deposition of immune complexes in the glomerular basement membrane and proteinuria. However, the molecular mechanisms underlying the glomerular inflammation of MN are not fully understood. This study was designed to investigate the role of clusterin (CLU) in the development of MN using a mouse model of cationic bovine serum albumin (cBSA)-induced MN.

Methods: Both wild-type C57BL/6j (WT) and CLU-knockout C57BL/6j (CLU-KO) mice were immunized with cBSA. The kidney function was determined by the levels of serum creatinine (SCr), blood urea nitrogen (BUN) and urinary protein. MN and glomerular deposits of CLU, complement C3 and immunoglobulins (Igs) were determined by histological analyses. Serum proteins were analyzed by the enzyme-linked immunosorbent assay, Western blot and liquid chromatography-mass spectrometry.

Results: Here, we showed that after cBSA immunization, SCr and proteinuria were increased in CLU-KO mice but not in WT mice. Similarly, severe glomerular atrophy and mesangial expansion along with C3 deposit were only found in the kidneys of CLU-KO mice but not in WT mice. However, there were no differences of serum IgG and complement 3 levels between CLU-KO and WT mice. In the serum of WT mice, CLU bound to anti-cBSA IgG, complements (eg, C8), proteinase/protease inhibitors and antioxidative proteins to form a complex, and incubation with WT serum reduced the complement-dependent lysis of podocytes in cultures.

Conclusion: Our data suggest that a CLU deficiency induces cBSA-initiated glomerular inflammation of MN in a disease-resistant strain of mice, suggesting an anti-glomerular inflammatory function of CLU in the resistance to MN development. This function may be at least in part due to the formation of CLU-anti-cBSA Igs complex that prevents glomerular inflammation or injury in the disease-resistant mice.

Keywords: glomerulonephritis; immune complex; inflammatory glomerular disease; membranous nephropathy; mouse model.