ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

ASN / Education & Meetings / Kidney Week /

Please note that you are viewing an archived section from 2023 and some content may be unavailable. To unlock all content for 2023, please visit the archives.

Abstract: SA-OR97

Humanized IGHA1 Mouse Induced by Lactobacillus casei Cell Wall Extract: A Novel Galactose-Deficient Immunoglobulin A1 (IgA1) Elevated Mouse Model of IgA Nephropathy

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Li, Run, Peking University First Hospital; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
  • Wang, Manliu, Peking University First Hospital; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
  • Xie, Xinfang, Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
  • Tian, Wenmin, Department of Biochemistry and Biophysics, Center for Precision Medicine Multi-Omics Research, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
  • Zhang, Yong, Institutes for Systems Genetics, West China Hospital, Sichuan University, Chengdu, China
  • Li, Jingyi, Peking University First Hospital; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
  • Dong, Yaping, Peking University First Hospital; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
  • Zan, Jincan, Peking University First Hospital; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
  • Jin, Jing, Department of Medicine, Division of Nephrology and Hypertension, Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Lv, Jicheng, Peking University First Hospital; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
  • Zhang, Hong, Peking University First Hospital; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
Background

IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. A ‘multi-hit’ hypothesis has been proposed to explain the pathogenesis of IgAN and galactose-deficient IgA1 (Gd-IgA1) was defined as the first hit. In this study, we constructed a novel Gd-IgA1 elevated mouse model with typical histopathology features of IgAN, by immunizing the immunoglobulin heavy constant alpha 1 knock-in (IGHA1+/+) mice with Lactobacillus casei Cell Wall Extract (LCWE).

Methods

IGHA1+/+ mice were generated by replacing the endogenous mouse Igha gene with the human IGHA1 gene via a CRISPR/Cas9 system. 2-month-old male IGHA1+/+ mice were injected i.p. with either 0.5mg/g LCWE plus complete Freund's adjuvant (CFA) or PBS eight times. 8-month-old mice were euthanized for further examination.

Results

IGHA1+/+ mice expressed human IgA1 heavy chain instead of mouse IgA. Human IgA, human IgA-mouse IgG complex, and CD89-binding pIgA1 complex levels were significantly increased from 4 months old in the serum of IGHA1+/+ mice induced by LCWE plus CFA compared with PBS. Meanwhile, as observations continued, the serum Gd-IgA1 absolute value and relative proportion to hIgA1 increased 4 times in IGHA1+/+-LCWE mice. We quantitatively analyzed the O-glycopeptides of human IgA1 hinge region (HR) using LC-MS analysis and found HR from IGHA1+/+-LCWE mice showed hypo-galactosylation than IGHA1+/+-PBS mice.
IGHA1+/+-LCWE mice showed a continuous and stable human IgA1 (positive rate: 100%) kidney mesangial deposition with C3 co-deposits (positive rate: 81.25%) until 8 months old. Histology demonstrated a significant rise in mesangial expansion and hypercellularity. Electron microscopy showed typical mesangial electron-dense deposits in IGHA1+/+-LCWE mice.

Conclusion

We established a novel serum Gd-IgA1 elevated mouse model presenting typical pathological characteristics of IgAN, which will be used to further explore the mechanisms and new therapeutic strategies.

Funding

  • Government Support – Non-U.S.