Abstract: TH-PO0291
RTN1A-RUVBL2 Signaling Promotes BMP4-Dependent Endoplasmic Reticulum Stress and Podocyte Injury in Diabetic Kidney Disease
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
- E, Jing, Department of Nephrology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China
- Zheng, Yali, Department of Nephrology, People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia, China
Background
Endoplasmic reticulum (ER) stress contributes to podocyte injury and progression of diabetic kidney disease (DKD). RTN1A has been implicated in ER stress activation during kidney injury; however, its podocyte-specific role and downstream signaling mechanisms in DKD remain unclear. We investigated whether RTN1A promotes DKD progression through RUVBL2-mediated ER stress signaling.
Methods
Podocyte-specific inducible RTN1A-overexpressing mice (Nephrin-rtTA;RTN1Aoe) were generated and subjected to streptozotocin-induced diabetes with or without unilateral nephrectomy. Renal injury, podocyte loss, apoptosis, and ER stress signaling were assessed by histologic and molecular analyses. RTN1A-interacting proteins were identified by co-immunoprecipitation coupled with mass spectrometry and validated by AlphaFold modeling and co-immunoprecipitation. Human DKD kidney tissues, cultured podocytes, and db/db mice with RUVBL2 overexpression were used to evaluate downstream mechanisms involving RUVBL2 and BMP4 signaling.
Results
Podocyte-specific RTN1A overexpression aggravated albuminuria, glomerular injury, podocyte depletion, and apoptosis in diabetic mice and was further exacerbated following unilateral nephrectomy, accompanied by enhanced PERK activation.
Protein interaction screening identified RUVBL2 as a downstream RTN1A-interacting protein, which was validated by AlphaFold modeling and co-immunoprecipitation. In human DKD tissues, RUVBL2 expression progressively increased with pathological severity and was associated with dysregulated ER stress signaling.
High glucose induced RUVBL2 expression and ER stress activation in podocytes. RUVBL2 overexpression enhanced PERK/IRE1 signaling, whereas RUVBL2 silencing attenuated RTN1A-mediated ER stress responses.Mechanistically, RUVBL2 interacted with BMP4 and promoted BMP4-dependent ER stress signaling under high-glucose conditions. Suppression of RUVBL2 reduced BMP4 expression and attenuated PERK/IRE1 activation.
In db/db mice, RUVBL2 overexpression aggravated glomerular injury and renal dysfunction, accompanied by activation of PI3K/AKT signaling, oxidative stress, and inflammatory responses.
Conclusion
RTN1A drives DKD progression through a RUVBL2-dependent mechanism linking ER stress to BMP4 activation and podocyte injury. The RTN1A–RUVBL2–BMP4 axis may represent a therapeutic target in DKD.
Acknowledgment
This work was supported by the National Natural Science Foundation of China （Grant No.8246030042）
Funding
- Government Support – Non-U.S.