Kidney Week

Abstract: TH-PO0361

Urinary Endoplasmic Reticulum (ER) Chaperones: Biomarkers of Glomerular ER Stress

Session Information

• Glomerular Diseases: Genetics to Therapeutics
  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

• Cybulsky, Andrey V., McGill University Health Centre, Montreal, Quebec, Canada

Andrey V. Cybulsky, MD

• Papillon, Joan, McGill University Health Centre, Montreal, Quebec, Canada

Joan Papillon

• Tousson-Abouelazm, Nihad, McGill University Health Centre, Montreal, Canada

Nihad Tousson-Abouelazm, MD, PhD

• Alam, Ahsan, McGill University Health Centre, Montreal, Quebec, Canada

Ahsan Alam, MD, MS

• Baroz, Frederic, McGill University Health Centre, Montreal, Quebec, Canada

Frederic Baroz, MD, MS, MSc

Background

Glomerulopathies (GN)/podocytopathies may feature impaired protein homeostasis in the endoplasmic reticulum (ER) of podocytes. Protein misfolding causing ER stress activates the unfolded protein response (UPR), a protective signaling network. Mesencephalic astrocyte-derived neurotrophic factor (MANF) and ERdj3/DNAJB11 are ER chaperones lacking the ER protein retention motif, and can be secreted from cells during the UPR. In earlier studies of rats with membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS), monitoring secretion of MANF or ERdj3 from podocytes into the urine identified glomerular ER stress/UPR activation. The present study addresses the biomarker potential of MANF and ERdj3 in human MN and FSGS.

Methods

Urinary ER chaperones were studied in patients with glomerular and non-glomerular diseases, and healthy controls. MANF and ERdj3 were measured in urine samples (standardized to 5 µg creatinine) by immunoblotting. Some samples were provided by NIDDK.

Results

Glomerular expression of MANF and ERdj3 mRNAs was increased significantly in human MN and FSGS (GSE108109 dataset). Urinary MANF and ERdj3 were increased (P<0.0001) in proteinuric MN and FSGS (↑UPCR), compared to MN and FSGS in remission (↓UPCR), as well as other GNs, polycystic kidney disease (PKD), hypertension (HTN) and healthy controls (arbitrary units; Table). Urine protein/creatinine ratios (UPCR; g/g) were greater (P<0.0001) in proteinuric MN and FSGS, compared to all other groups. In individual patients with proteinuric MN or FSGS, urinary MANF and ERdj3 correlated only weakly with UPCR; correlation of MANF with ERdj3 was moderate. Males represented ~60% of persons in each group. eGFR in proteinuric MN and FSGS was >40 ml/min/1.73 m². In MN, there were no significant differences in urinary MANF and ERdj3 between anti-PLA2R positive (N=17) and negative individuals (N=6).

Conclusion

Proteinuric MN and FSGS show increased glomerular expression of MANF and ERdj3, and high urinary levels of these ER chaperones, which correlate only weakly with UPCR. The results support the view that in these podocytopathies, urinary ER chaperones are non-invasive biomarkers of glomerular/podocyte ER stress. Such biomarkers may eventually be useful in identifying patients for therapies targeting ER protein misfolding.

Funding

• Private Foundation Support