Kidney Week

Abstract: TH-PO0265

Non-HIV Collapsing Glomerulopathy in Hispanic Patients Is Mediated by Genomic Defects Upstream of ZHX2 and Low Glomerular Endothelial ITGB5 Expression

Session Information

• Glomerular Diseases: Cell Biology
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Ortega Lozano, Ariadna Jazmin, Rush University, Chicago, Illinois, United States

Ariadna Jazmin Ortega Lozano, PhD

• Sanchez Gloria, Jose Luis, Rush University, Chicago, Illinois, United States

Jose Luis Sanchez Gloria, PhD

• Das, Ranjan, Rush University, Chicago, Illinois, United States

Ranjan Das, PhD

• Kharlyngdoh, Joubert Banjop, Rush University, Chicago, Illinois, United States

Joubert Banjop Kharlyngdoh, PhD

• Molina-Jijon, Eduardo, Rush University, Chicago, Illinois, United States

Eduardo Molina-Jijon, MSc, PhD

• Clement, Lionel C., Rush University, Chicago, Illinois, United States

Lionel C. Clement, PhD

• Mace, Camille E., Rush University, Chicago, Illinois, United States

Camille E. Mace, PhD

• Avila-Casado, Carmen, University Health Network, Toronto, Ontario, Canada

Carmen Avila-Casado, MD, PhD

• Chugh, Sumant S., Rush University, Chicago, Illinois, United States

Sumant S. Chugh, MD, FASN

Group or Team Name

• Glomerular Disease Therapeutics Laboratory

Background

ZHX proteins are cell membrane bound transcriptional factors that enter the podocyte nucleus during disease pathogenesis. ZHX2 plays a pivotal role in MCD, FSGS and collapsing glomerulopathy (CG) pathogenesis. Whereas specific Insertions and Deletions (InDels) upstream of ZHX2 cause a ZHX2 hypomorph state in human MCD, transgenic overexpression of ZHX2 in podocytes predisposes to CG. All of our Peruvian patients with CG from COVID-19 had specific InDels upstream of ZHX2 at sites different from MCD patients.

Methods

Combination of CRISPR/Cas9 in IPS cells and in vivo models of CG

Results

We replicated two out of three shared InDels from these CG patients in IPS cells using CRISPR/Cas9, which resulted in ZHX2 upregulation, proving that human CG is a high ZHX2 expression state. Next, we discovered that low glomerular endothelial Itgb5 expression predisposes to CG, since injection of serum from Hispanic patients with recurrent CG or γ2-NTS into Itgb5^-/- mice causes CG. Incubating cultured glomerular endothelial cells directly with serum from Hispanic CG patients had no effect on Itgb5 expression. However, using media conditioned by incubating it first with cultured podocytes and then with cultured endothelial cells resulted in Itgb5 downregulation. This suggests that soluble factor mediated cross talk between podocytes and endothelial cells in CG results in Itgb5 down regulation. Next, we studied the Rrm2b ^-/- mouse model of CG, in which proteinuria develops in female mice after 7 weeks and CG around age 10 weeks, with mice dying of CG between 12-13 weeks. Gene expression analysis determined that Itgb5 downregulation coincides with development of CG at 10 weeks. To study the significance of Itgb5 in the development of loop collapse, we generated dual Rrm2b^-/-; Itgb5^-/- mice. In contrast to Rrm2b^-/- mice, dual Rrm2b^-/-; Itgb5^-/- female mice had severe albuminuria at age 6 weeks and died of CG at around age 8 weeks. Finally, parvovirus infected rats developed high glomerular Zhx2 and low Itgb5 expression, but were otherwise healthy. Injection of human CG serum from Hispanic patients in infected, but not clean rats, resulted in CG, thereby mimicking the scenario of Parvovirus B19 related CG.

Conclusion

In summary, high podocyte ZHX2 and low endothelial Itgb5 expression are major mediators of CG in Hispanic patients.

Acknowledgment

R01DK111102, R01DK145476

Funding

• NIDDK Support