Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease
Kayaho Maeda, … , Maria G. Tsokos, George C. Tsokos
Kayaho Maeda, … , Maria G. Tsokos, George C. Tsokos
Published July 9, 2018
Citation Information: J Clin Invest. 2018;128(8):3445-3459. https://doi.org/10.1172/JCI99507.
View: Text | PDF
Research Article Autoimmunity Nephrology

CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease

  • Text
  • PDF
Abstract

Podocyte malfunction occurs in autoimmune and nonautoimmune kidney disease. Calcium signaling is essential for podocyte injury, but the role of Ca2+/calmodulin–dependent kinase (CaMK) signaling in podocytes has not been fully explored. We report that podocytes from patients with lupus nephritis and focal segmental glomerulosclerosis and lupus-prone and lipopolysaccharide- or adriamycin-treated mice display increased expression of CaMK IV (CaMK4), but not CaMK2. Mechanistically, CaMK4 modulated podocyte motility by altering the expression of the GTPases Rac1 and RhoA and suppressed the expression of nephrin, synaptopodin, and actin fibers in podocytes. In addition, it phosphorylated the scaffold protein 14-3-3β, which resulted in the release and degradation of synaptopodin. Targeted delivery of a CaMK4 inhibitor to podocytes preserved their ultrastructure, averted immune complex deposition and crescent formation, and suppressed proteinuria in lupus-prone mice and proteinuria in mice exposed to lipopolysaccharide-induced podocyte injury by preserving nephrin/synaptopodin expression. In animals exposed to adriamycin, podocyte-specific delivery of a CaMK4 inhibitor prevented and reversed podocyte injury and renal disease. We conclude that CaMK4 is pivotal in immune and nonimmune podocyte injury and that its targeted cell-specific inhibition preserves podocyte structure and function and should have therapeutic value in lupus nephritis and podocytopathies, including focal segmental glomerulosclerosis.

Authors

Kayaho Maeda, Kotaro Otomo, Nobuya Yoshida, Mones S. Abu-Asab, Kunihiro Ichinose, Tomoya Nishino, Michihito Kono, Andrew Ferretti, Rhea Bhargava, Shoichi Maruyama, Sean Bickerton, Tarek M. Fahmy, Maria G. Tsokos, George C. Tsokos

×

Figure 6

CaMK4 regulates podocyte migration.

Options: View larger image (or click on image) Download as PowerPoint
CaMK4 regulates podocyte migration.
(A) Result of Transwell migration ex...
(A) Result of Transwell migration experiments using human podocytes treated with control or CaMK4 siRNA. Error bars represent mean ± SEM (n = 3 independent experiments). *P < 0.05, Student’s t test. (B) Representative images of wound-healing assay 0, 12, and 24 hours after wounding. (C) Quantification of the results in B. Error bars represent mean ± SEM (n = 3 independent experiments). *P < 0.05, Student’s t test. (D and E) Western blotting analysis of GTP-Rac1 and total Rac1 expression (D) and GTP-RhoA and total RhoA (E) in human podocytes treated with control or CaMK4 siRNA for the indicated times. Three independent experiments were performed.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts