Kidney Week

Abstract: TH-PO0362

ERK1/2 Phosphorylation Drives Podocyte Injury Across Diverse Kidney Diseases

Session Information

• Glomerular Diseases: Genetics to Therapeutics
  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

• Morinishi, Takuya, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Takuya Morinishi, MD

• Yamada, Ryo, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Ryo Yamada, MD

• Iwashige, Yohei, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Yohei Iwashige, MD

• Muro, Koji, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Koji Muro, MD

• Konishi, Ryo, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Ryo Konishi

• Morita, Keisuke, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Keisuke Morita, MD

• Ikeda, Hiroyuki, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Hiroyuki Ikeda

• Kosaka, Tatsuaki, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Tatsuaki Kosaka, MD

• Yamamoto, Shinya, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Shinya Yamamoto, MD, PhD

• Yamada, Yasuhiro, Tokyo Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Bunkyo, Tokyo, Japan

Yasuhiro Yamada, MD, PhD

• Yanagita, Motoko, Kyoto Daigaku Daigakuin Igaku Kenkyuka Igakubu, Kyoto, Kyoto Prefecture, Japan

Motoko Yanagita, MD, PhD

Background

Podocyte injury is a common feature across diverse kidney diseases, yet unifying molecular mechanism remains elusive. Although in vitro studies suggest that phosphorylation of ERK1/2 (p-ERK1/2) plays a role in podocyte injury, its in vivo pathogenic role in podocytes has not been elucidated.

Methods

We established doxycycline-inducible, podocyte-specific transgenic mice in which ERK1/2 is constitutively phosphorylated and corresponding cell lines. 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

p-ERK1/2-positive podocytes were consistently observed across diverse human kidney diseases and mouse models of kidney injury. Podocyte specific ERK1/2 phosphorylation in transgenic mice let to progressive proteinuria and kidney dysfunction. Histological examination revealed significant podocyte hypertrophy, foot process effacement, and sequential podocyte detachment—morphological changes highly reminiscent of human focal segmental glomerulosclerosis. Additionally, immunohistochemistry revealed that ERK1/2-phosphorylated podocytes expressed cell cycle arrest markers (p16, p21, and p53) and LAMP1 (indicating an accumulation of lysosomal proteins), demonstrating cellular senescence-like features. PIC RNA-seq analysis revealed that ERK1/2 activation in podocytes significantly altered gene expression associated with cell motility, focal adhesion, and actin filament organization. In podocyte cell lines, ERK1/2 phosphorylation increased cell motility, reduced focal adhesions, and induced actin cytoskeleton remodeling, corroborating the in vivo findings.

Conclusion

Phosphorylation of ERK1/2 in podocytes is sufficient to drive podocyte injury by promoting cell motility, actin filament re-organization, and cellular senescence-like features. This activation of ERK1/2 represents a potentially universal pathogenic mechanism, suggesting it as a promising therapeutic target for glomerular diseases characterized by podocyte injury.