About

Shuta Ishibe, MD, is the Section Chief of Nephrology and a Professor of Medicine (Nephrology) at Yale School of Medicine. His major research interests include the endocytic process and matrix regulation in podocytes, which are specialized epithelial cells critical for maintaining the glomerular filtration barrier. His laboratory has identified the essential role of clathrin-coated endocytic processes in podocyte development and maintenance, demonstrating that in vivo models with gene ablations related to endocytosis develop severe proteinuria and foot process effacement. His work visualizes proteins involved in endocytosis and actin cytoskeleton interactions, focusing on understanding the critical factors being endocytosed in podocytes. Additionally, he investigates cell-matrix interactions, particularly the role of focal adhesion proteins and integrins in podocyte adhesion and motility during health and disease states, utilizing mouse genetic models of disease. His research aims to elucidate mechanisms underlying podocyte injury, proteinuria, and nephrotic syndrome, with ongoing efforts to identify therapeutic targets and understand disease mutations through human sample analysis.

Research topics

• Medicine
• Chemistry
• Cell biology
• Biochemistry
• Internal medicine
• Biology
• Cancer research

Selected publications

• Principles of cell signaling

  Elsevier eBooks · 2026-01-01

  book-chapter1st authorCorresponding
  PublisherDOI

• Loss of Cyclin G–Associated Kinase (Gak) Leads to Lysosome Dysfunction and Immune Modulation in Podocytes

  Journal of the American Society of Nephrology · 2026-05-18

  articleOpen accessSenior author

  BACKGROUND: Given the post-mitotic nature of podocytes, adapting to both physiological and pathological stress is crucial to prevent podocyte loss. An important component of maintaining cellular homeostasis are lysosomes, which are membrane-bound organelles responsible for degradation and recycling of damaged organelles and other macromolecules. Lysosome impairment has been shown to cause cellular and organ dysfunction, highlighting its crucial role in homeostasis. METHODS: We previously showed that podocyte-specific loss of cyclin G-associated kinase (Gak-KO) leads to severe proteinuria, podocyte injury, and kidney failure. To interrogate which GAK domains are necessary for its function, we utilized a transgenic mouse expressing a truncated 62-kDa C-terminal GAK protein (GAK C62), which consists of the clathrin-binding and J domains. We evaluated the functional role of GAK C62 in podocytes using immunofluorescence, western blotting, and in vivo transcriptomic analysis. RESULTS: Our findings revealed significant accumulation of autophagic vesicles in Gak-KO podocytes. By systematically probing for potential causes of autophagosome accumulation, we showed that loss of Gak resulted in impaired lysosomal degradation, secondary to mistrafficking of lysosomal hydrolases. Notably, GAK C62 expression completely rescued these phenotypes at the cellular and organismal levels. Moreover, in vivo TRAP-seq and cytokine profiling demonstrated enrichment of immune-related pathways and IL-11 production in Gak-KO podocytes. CONCLUSIONS: GAK, specifically its C-terminal domains, plays an important role in podocyte lysosome homeostasis. Lysosomal dysfunction due to loss of Gak may lead podocytes to adopt immune-like properties characterized by the release of pro-inflammatory cytokine IL-11.

  PublisherDOI

• List of contributors

  Elsevier eBooks · 2026-01-01

  book-chapter
  PublisherDOI

• G1 and G2 ApolipoproteinL1 modulate macrophage inflammation and lipid accumulation through the polyamine pathway

  eLife · 2025-07-17 · 1 citations

  articleOpen access

  Abstract The G1 and G2 variants of the gene encoding Apolipoprotein L1 (APOL1) increase risk for kidney disease and cardiometabolic traits. While previous studies have elucidated key mechanisms by which G1 and G2 APOL1 cause cellular inflammation and cytotoxicity, it remains unclear whether these mechanisms drive inflammation in G1 and G2 macrophages. In this study, we used mouse bone-marrow-derived macrophages and human induced pluripotent stem cell-derived macrophages to identify altered immune signaling and inflammatory activation caused by G1 and G2 APOL1. We demonstrated that G1 and G2 APOL1 increased lipid accumulation, pro-inflammatory cytokine expression, and inflammasome signaling; this inflammatory response was sustained when treated with anti-inflammatory cytokines IL-4 and IL-10. Additionally, in G1 and G2 macrophages we observed increased mitochondrial size and elongation, oxidative phosphorylation, and glycolysis. Finally, we used unbiased metabolite analysis to identify an accumulation of polyamine spermidine and the enrichment of the spermidine synthesis pathway in G1 and G2 macrophages. When treated with polyamine inhibitor α-difluoromethylornithine (DFMO), lipid accumulation and inflammasome gene expression decreased in G1 and G2 macrophages. Together, these findings establish the pro-inflammatory effects of G1 and G2 APOL1 in macrophages and identify a novel pathway which ameliorates G1 and G2 effects on cellular inflammation.

  PublisherDOI

• A T-cell intrinsic Role for <i>APOL1</i> Risk Alleles in Allograft Rejection

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-18

  preprintOpen access

  Abstract African Americans have an increased risk of kidney disease due to exonic variants in Apolipoprotein-L1 (G1 and G2). These prevalent variants have also been linked with kidney rejection, but outside of association with African ancestry, underpinning causal mechanisms are unknown. We investigated T-cell function using transgenic mice with physiologic expression of wild type (G0-), G1-, or G2-APOL1. Mice with variant APOL1 showed greater CD8+T-cell activation with expansion of a central memory (TCM) subset. Stimulated G1-CD8+T-cells showed enhanced proliferation and cytokine production, which reversed with APOL1 inhibition. In MHC-mismatched cardiac transplants, G1-mice demonstrated greater CD8+T-cell infiltration and reduced survival. Bulk transcriptome of G1-CD8+T-cells, and single-cell transcriptome of graft infiltrating TCMs, showed enrichment of canonical T-cell receptor (TCR) pathways including Ca 2+ -signaling. G1-CD8+T-cells demonstrated baseline ER-Ca 2+ depletion followed by sustained increases in cytosolic-Ca 2+ upon TCR stimulation. G1-CD8+T-cells were more sensitive to Ca 2+ chelation, or store-operated Ca 2+ entry inhibition, and relatively resistant to calcineurin antagonism vs. G0-CD8+T-cells. Analogously, in a kidney transplant cohort, APOL1-variant recipients developed rejection when they had elevated peripheral TCMs before transplantation and despite significantly higher tacrolimus levels vs G0/G0-AAs with rejection. In summary, we unravel an excitatory T-cell intrinsic mechanism for APOL1 exonic variants, causally linking them with kidney rejection.

  PublisherOA PDFDOI

• CRB2 depletion induces YAP signaling and disrupts mechanosensing in podocytes

  American Journal of Physiology-Renal Physiology · 2025-03-10 · 3 citations

  articleOpen access

  We identified a rare compound heterozygous CRB2 mutation as the cause of familial SRNS/FSGS in a two-generation East Asian kindred. Modeling the effect of the mutation, we show that CRB2 knockdown in podocytes induces YAP transcriptional activity and upregulates YAP-mediated mechanosignaling. Using elastic resonator interference stress microscopy (ERISM), we demonstrate that CRB2 knockdown enhances podocyte contractility in a substrate stiffness-dependent manner. The knockdown effect decreases with increasing substrate stiffness, indicating impaired mechanosensing in CRB2 -deficient podocytes.

  PublisherOA PDFDOI

• GIT ArfGAP2: A Cytoskeletal Safeguard in Podocytes

  Journal of the American Society of Nephrology · 2025-04-18

  article1st authorCorresponding
  PublisherDOI

• APOL1 Variants Promote T Cell Excitation by Modulating Calcium (Ca2+) Signaling Downstream of T Cell Receptors (TCRs) in Graft Rejection

  Journal of the American Society of Nephrology · 2025-10-01

  article
  PublisherDOI

• G1 and G2 ApolipoproteinL1 modulate macrophage inflammation and lipid accumulation through the polyamine pathway

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-09 · 1 citations

  preprintOpen access

  Abstract The G1 and G2 variants of the gene encoding Apolipoprotein L1 ( APOL1 ) increase risk for kidney disease and cardiometabolic traits. While previous studies have elucidated key mechanisms by which G1 and G2 APOL1 cause cellular inflammation and cytotoxicity, it remains unclear whether these mechanisms drive inflammation in G1 and G2 macrophages. In this study, we used mouse bone-marrow-derived macrophages and human induced pluripotent stem cell-derived macrophages to identify altered immune signaling and inflammatory activation caused by G1 and G2 APOL1 . We demonstrated that G1 and G2 APOL1 increased lipid accumulation, pro-inflammatory cytokine expression, and inflammasome signaling; this inflammatory response was sustained when treated with anti-inflammatory cytokines IL-4 and IL-10. Additionally, in G1 and G2 macrophages we observed increased mitochondrial size and elongation, oxidative phosphorylation, and glycolysis. Finally, we used unbiased metabolite analysis to identify an accumulation of polyamine spermidine and the enrichment of the spermidine synthesis pathway in G1 and G2 macrophages. When treated with polyamine inhibitor α-difluoromethylornithine (DFMO), lipid accumulation and inflammasome gene expression decreased in G1 and G2 macrophages. Together, these findings establish the pro-inflammatory effects of G1 and G2 APOL1 in macrophages and identify a novel pathway which ameliorates G1 and G2 effects on cellular inflammation.

  PublisherOA PDFDOI

• G1 and G2 ApolipoproteinL1 modulate macrophage inflammation and lipid accumulation through the polyamine pathway

  eLife · 2025-07-17

  articleOpen access

  Abstract The G1 and G2 variants of the gene encoding Apolipoprotein L1 (APOL1) increase risk for kidney disease and cardiometabolic traits. While previous studies have elucidated key mechanisms by which G1 and G2 APOL1 cause cellular inflammation and cytotoxicity, it remains unclear whether these mechanisms drive inflammation in G1 and G2 macrophages. In this study, we used mouse bone-marrow-derived macrophages and human induced pluripotent stem cell-derived macrophages to identify altered immune signaling and inflammatory activation caused by G1 and G2 APOL1. We demonstrated that G1 and G2 APOL1 increased lipid accumulation, pro-inflammatory cytokine expression, and inflammasome signaling; this inflammatory response was sustained when treated with anti-inflammatory cytokines IL-4 and IL-10. Additionally, in G1 and G2 macrophages we observed increased mitochondrial size and elongation, oxidative phosphorylation, and glycolysis. Finally, we used unbiased metabolite analysis to identify an accumulation of polyamine spermidine and the enrichment of the spermidine synthesis pathway in G1 and G2 macrophages. When treated with polyamine inhibitor α-difluoromethylornithine (DFMO), lipid accumulation and inflammasome gene expression decreased in G1 and G2 macrophages. Together, these findings establish the pro-inflammatory effects of G1 and G2 APOL1 in macrophages and identify a novel pathway which ameliorates G1 and G2 effects on cellular inflammation.

  PublisherOA PDFDOI

Recent grants

• Role of LRP1 in Podocyte Biology

  NIH · $5.1M · 2012–2028

• Disease Models and Mechanisms Core

  NIH · $27.2M · 2008–2024

• Role of Calpains in Podocyte Biology

  NIH · $5.4M · 2010–2027

Frequent coauthors

• Xuefei Tian

  Yale University

  20 shared

• Kazunori Inoue

  Osaka University

  13 shared

• Lewis C. Cantley

  Dana-Farber Cancer Institute

  12 shared

• Akashi Togawa

  Shizuoka Saiseikai General Hospital

  11 shared

• K. Soda

  Nippon Medical School

  9 shared

• Madhav C. Menon

  Yale University

  9 shared

• Xiaohua Peng

  First Affiliated Hospital of University of South China

  9 shared

• Dominique Joly

  University of Zurich

  8 shared

Labs

• Ishibe LabPI