Abstract: TH-PO0336
Podocyte Retroelement Activation Links Albuminuria to Depression-Related Neuroimmune Changes Through Blood-Brain Barrier Dysfunction and Th1 Skewed CD4 T-Cell Brain Entry
Session Information
- Glomerular Diseases: Omics
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
- Iwabuchi, Seiei, Keio Gijuku Daigaku Igakubu Daigakuin Igaku Kenkyuka Naikagaku Kyoshitsu, Shinjuku, Tokyo, Japan
- Nakamichi, Ran, Keio Gijuku Daigaku Igakubu Daigakuin Igaku Kenkyuka Naikagaku Kyoshitsu, Shinjuku, Tokyo, Japan
- Hayashi, Kaori, Keio Gijuku Daigaku Igakubu Daigakuin Igaku Kenkyuka Naikagaku Kyoshitsu, Shinjuku, Tokyo, Japan
Background
Albuminuria is associated with depression independent of eGFR, but how podocyte injury affects the brain is unclear. We reported that podocyte DNA damage induces T-cell activation and may contribute to extra-renal injury via systemic immune remodeling. As DNA damage may derepress retroelements and activate immunity, we investigated whether podocyte retroelement activation induces brain alterations through a kidney–immune–brain axis.
Methods
We generated podocyte-specific Trim28 knockout (Trim28KO) mice, targeting Trim28, an epigenetic retroelement-silencing corepressor reduced in DNA-damaged podocytes. We assessed podocyte retroelement activation and its effects on systemic immune remodeling and brain alterations.
Results
Trim28KO mice developed albuminuria from 6 weeks with foot-process effacement and preserved serum creatinine. Podocyte Trim28 deletion activated retroelements, including LINE-1, and induced podocyte IFNβ, indicating retroelement-associated innate immunity. This was accompanied by kidney-to-systemic expansion of CD44+PD-1+ CD4+ T cells with a chronic activation/exhaustion-like phenotype, increased CD153+PD-1+ senescence-associated CD4+ T cells, and elevated serum IFNγ and osteopontin, suggesting adaptive immune activation. Trim28KO mice exhibited depression-related brain alterations, including reduced Y-maze activity and abnormal ΔFosB mapping with global hypoactivity and focal hyperactivation in the hippocampus and paraventricular thalamus. These were accompanied by blood–brain barrier (BBB)-related perivascular GFAP+ astrogliosis and inflammatory microglial remodeling (Gpnmb, Spp1, Cst7, Irf7 upregulation). CD6 was enriched on PD-1+ CD4+ T cells, and brain CD4+ T cells showed an IFNγ+CXCR3-high Th1-skewed profile. Brain endothelial ALCAM was upregulated with systemic cytokine elevation, suggesting CD6–ALCAM-associated Th1-skewed CD4+ T-cell brain entry.
Conclusion
Podocyte retroelement activation links albuminuria to depression-related neuroimmune changes despite preserved renal function, positioning it as a potential upstream driver of a kidney–immune–brain axis. Systemic CD4+ T-cell remodeling may converge with BBB-related endothelial activation to facilitate CD6-ALCAM-associated brain entry of Th1-skewed CD4+ T cells, highlighting this pathway as a candidate therapeutic target.