Kidney Week 2025 Annual Meeting-Extending Glomerular Function in Aging

Video Transcription

Video Summary

The session focused on how aging disrupts the glomerular filtration barrier, with emphasis on podocytes and glomerular endothelial cells and on potentially targetable pathways.<br /><br />Mariah Sweetwyne presented a podocyte-specific mitochondrial “mitotag” mouse enabling isolation of podocyte mitochondria from whole kidney. Despite low mitochondrial abundance, podocyte mitochondria showed unexpectedly high respiratory capacity. Culturing podocytes rapidly impaired mitochondrial respiration and increased ROS, cautioning against culture-based metabolic conclusions. In natural aging, mitochondrial number stayed stable, but male podocytes showed reduced respiratory capacity. A cardiolipin-stabilizing peptide (SS31/eleamipretide) modestly improved proteinuria in males on a high-fat/high-sucrose diet, consistent with sex-specific mitochondrial aging. Proteomic crosslinking suggested podocyte mitochondria are uniquely integrated with detoxification, lysosomes, and cytoskeleton, and aconitase activity declined with age.<br /><br />Daniel Jane Witt described an endothelial-cell protein, Z521, highly expressed in young glomerular endothelium but lost with aging. Endothelial-specific Z521 knockout mice developed proteinuria, reduced GFR, endothelial swelling, basement membrane thickening, altered junctional proteins, and systemic barrier leak. Mechanistically, Z521 supports AKT–eNOS signaling and nitric oxide–mediated podocyte–endothelial crosstalk via endosomal/Golgi trafficking.<br /><br />Dr. Gong argued GSK3β is enriched in podocytes, rises in aging and glomerular diseases, and promotes podocyte senescence via p16/p53 pathways. Podocyte-specific GSK3β knockout reduced age-related proteinuria and preserved podocyte number. He proposed “micro-dose” lithium (a GSK3β inhibitor) could be renoprotective despite known nephrotoxicity at psychiatric doses, presenting supportive mouse and small human observational data.<br /><br />Finally, Dr. Wesley used large-scale single-nucleus RNA-seq to show podocyte aging is a continuum rather than a discrete state, with injury pushing cells toward senescent/inflammatory programs. Because senolytics would worsen podocyte loss, he emphasized senomorphics (SASP modulation). He highlighted PD-1 pathway blockade and a design-of-experiments screening approach to identify multi-factor anti-SASP combinations that reduce podocyte injury and death.

Asset Subtitle

Moderator(s): Nicole Endlich, Ilse Daehn

Presentation(s):

Age-Dependent Mitochondrial Function in Podocytes - Mariya Sweetwyne
Glomerular Endothelial Cells in Aging-Related Glomerular Filtration Barrier Dysfunction - Dan Jane-Wit
Glycogen Synthase Kinase-3 Beta and the Aging Glomerulus - Rujun Gong
Reversing the Aged Phenotype - Oliver Wessely

Support for all sessions in the Glomerular Diseases Learning Pathway is provided by an educational grant from Vera Therapeutics, Inc.

Meta Tag

Date 11/7/2025

Pathway 1 Glomerular Diseases

Pathway 2 CKD Non-Dialysis

Session ID 507311

Keywords

glomerular filtration barrier aging

podocyte mitochondrial function

glomerular endothelial cells

mitotag mouse model

podocyte mitochondrial respiration

reactive oxygen species (ROS)

SS31 (elamipretide) cardiolipin peptide

sex-specific mitochondrial aging

aconitase activity decline

Z521 endothelial protein

AKT–eNOS signaling

nitric oxide podocyte–endothelial crosstalk

GSK3β podocyte senescence

micro-dose lithium renoprotection

single-nucleus RNA-seq podocyte aging continuum