Kidney Week 2025 Annual Meeting-New Paradigms in Proteinuric Kidney Diseases

Video Transcription

Video Summary

The session on “new paradigms in protein-related kidney diseases” featured several talks highlighting novel mechanisms and therapeutic targets across glomerular disorders.<br /><br />Shuta Ishibe reviewed “mitotic catastrophe” as a podocyte fate after injury: stressed, normally quiescent podocytes re-enter the cell cycle, develop DNA damage, abnormal chromosome segregation, multinucleation, and ultimately detach or die—contributing to podocyte depletion and FSGS progression. Evidence includes multinucleated podocytes in human biopsies (FSGS, cystinosis), animal models, and urinary podocytes. Mechanistic regulators discussed included MDM2–p53/p21, KLF4, GSK3α/β via Hippo/YAP signaling, and the mechanosensor Piezo1. Ishibe presented new data showing podocyte-specific Profilin1 loss causes severe proteinuria, glomerulosclerosis, widespread multinucleation, γH2AX DNA damage, reduced p53/p21, and cell-cycle entry (FUCCI reporters). TRAP-seq identified reduced RRP8; re-expression partially rescued multinucleation/DNA damage. In patient biopsies, multinucleated podocytes occurred in a subset of diseases, without strong correlation to proteinuria severity. Discussion focused on early markers and podocyte-targeted delivery to avoid systemic cell-cycle inhibition risks.<br /><br />Reiko Inagi emphasized organelle stress and inter-organelle crosstalk in metabolic kidney injury. She outlined how maladaptive UPR, ER–mitochondria contacts (MAM), and ER signaling (including STING) link metabolism, inflammation, and fibrosis. Her group showed lysophosphatidylcholine accumulation in diabetic kidney disease disrupts ER–mitochondria contacts and promotes tubular lipotoxicity; IP3R also influences tubular cell-cycle responses in a calcium-independent manner. She highlighted PDZD8-mediated ER–endolysosome tethering: podocyte PDZD8 loss worsened lipid (glycosphingolipid) accumulation and lipotoxicity, while systemic PDZD8 loss unexpectedly reduced cisplatin AKI inflammation via impaired endosomal maturation/NF-κB signaling.<br /><br />Julien Canon presented PI3Kα (PIK3CA) activation as a driver of proliferative podocytopathy. A patient with somatic PIK3CA gain-of-function in kidney cells had proteinuria that improved/stabilized with the PI3Kα inhibitor alpelisib. Podocyte-specific PIK3CA-mutant mice developed progressive proteinuria, podocyte dedifferentiation, Ki67 positivity, inflammation, and sclerosis; alpelisib improved proteinuria and histology, with some reversibility, and also benefited collapsing glomerulopathy (TG26) and lupus nephritis models. Unexpectedly, alpelisib reduced immune complex deposition, anti-dsDNA antibodies, and inflammatory cytokines, and inhibited activated T/B cells from lupus nephritis patients ex vivo. Safety concerns (notably hyperinsulinemia) were discussed, suggesting low-dose or improved agents.<br /><br />Arteel Sedan focused on glomerular endothelial–podocyte crosstalk in proteinuric disease. Using conditional knockouts, her team showed endothelial ETA receptor signaling contributes early to Adriamycin injury, driving mitochondrial dysfunction, glycocalyx loss, endothelial ultrastructural damage, and subsequent podocyte depletion; endothelial ETA deletion protected glomeruli. Podocyte-derived endothelin-1 was also required for injury in Adriamycin and podocyte TGFβ-activation models, and diffusion modeling supported ET-1 movement across the filtration barrier. She then described an endothelial-secreted “podocyte cytotoxic factor” (PCF) identified by proteomics, elevated in multiple models and in human disease/urine, internalized by podocytes and altering cytoskeleton (likely via integrin β3). PCF blockade (morpholino in zebrafish; shRNA/EC-specific knockout in mice) reduced proteinuria and glomerular injury, suggesting a new endothelial-derived therapeutic target.

Asset Subtitle

Moderator(s): Sandeep Mallipattu, Mario Schiffer

Presentation(s):

Mitotic Catastrophe in Glomerular Diseases - Shuta Ishibe
Maintaining Mitochondrial and Endosomal Homeostasis During Podocyte Lipotoxicity - Reiko Inagi
PI3K Pathway Antagonists in Proliferative Podocytopathy - Guillaume Canaud
Evolving Paradigms in Proteinuric Diseases and the Role of the Glomerular Endothelium - Ilse Daehn

ASN thanks the Japanese Society of Nephrology (JSN) and JSN Ambassador, Dr. Reiko Inagi.

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

Meta Tag

Date 11/8/2025

Pathway 1 Glomerular Diseases

Pathway 2 CKD Non-Dialysis

Session ID 507321

Keywords

protein-related kidney diseases

glomerular disorders

podocyte injury

mitotic catastrophe

focal segmental glomerulosclerosis (FSGS)

podocyte cell-cycle re-entry

DNA damage (γH2AX)

Hippo/YAP signaling

Piezo1 mechanosensor

Profilin1 (PFN1)

ER stress and unfolded protein response (UPR)

ER–mitochondria contacts (MAM)

PI3Kα (PIK3CA) gain-of-function

alpelisib

endothelin-1/ETA receptor signaling