Abstract: FR-PO0799
Phosphorylation of ERK1/2 Induces Detachment of Podocytes, Leading to Collapsing FSGS
Session Information
- Glomerular Diseases: Cell Homeostasis and Novel Injury Mechanisms
November 07, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology
Authors
- Morinishi, Takuya, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan
- Yamada, Ryo, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan
- Morita, Keisuke, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan
- Konishi, Ryo, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan
- Iwashige, Yohei, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan
- Muro, Koji, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan
- Yamamoto, Shigenori, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan
- Yamamoto, Shinya, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan
- Yamada, Yasuhiro, Tokyo Daigaku, Bunkyo, Tokyo, Japan
- Yanagita, Motoko, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan
Background
Phosphorylation of ERK1/2 (p-ERK1/2) has been suggested to play a role in podocyte injury; however, the majority of supporting evidence originates from in vitro studies, leaving the role of p-ERK1/2 in podocytes in vivo insufficiently elucidated.
Methods
We established transgenic mice and cell lines in which ERK1/2 is constitutively phosphorylated in a doxycycline-dependent manner specifically within podocytes. Furthermore, we conducted podocyte-specific spatial transcriptomic analysis using photo-isolation chemistry (PIC) to investigate gene alterations associated with ERK1/2 phosphorylation in vivo. Additionally, we examined p-ERK1/2 expression in podocytes in both experimental models of podocyte injury and human kidney diseases.
Results
In wild-type mice, p-ERK1/2 was identified in a subset of podocytes with aging and in the adriamycin nephropathy model. Similarly, p-ERK1/2-positive podocytes were observed in various human kidney diseases, including focal segmental glomerulosclerosis (FSGS). Transgenic mice constitutively expressing p-ERK1/2 in podocytes developed progressive proteinuria and kidney dysfunction. Histological examination revealed significant podocyte hypertrophy, cytoplasmic vacuolization, foot process effacement, and sequential podocyte detachment—morphological changes highly reminiscent of human collapsing FSGS. PIC-RNAseq analysis revealed that ERK1/2 activation in podocytes significantly altered the expression of gene clusters associated with cell motility, focal adhesion, and actin filament organization. In podocyte cell lines, ERK1/2 phosphorylation enhanced cell motility, induced remodeling of the actin cytoskeleton, and reduced the number of focal adhesion sites, corroborating the in vivo findings.
Conclusion
Phosphorylation of ERK1/2 in podocytes induces alterations in cellular structure and function, facilitating increased motility and reduced adhesion, which ultimately leads to podocyte detachment. These processes may culminate in the onset of collapsing FSGS. Our findings underscore the role of ERK1/2 signaling as a pivotal mediator of podocyte pathology and suggest it as a potential therapeutic target in glomerular diseases characterized by podocyte injury and loss.