CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease

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

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 lupusprone 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.

Original languageEnglish
Pages (from-to)3445-3459
Number of pages15
JournalJournal of Clinical Investigation
Volume128
Issue number8
DOIs
Publication statusPublished - 2018 Aug 1
Externally publishedYes

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Podocytes
Kidney Diseases
Focal Segmental Glomerulosclerosis
Calcium-Calmodulin-Dependent Protein Kinases
Lupus Nephritis
Wounds and Injuries
Proteinuria
Doxorubicin
Lipopolysaccharides
14-3-3 Proteins
Calcium Signaling
GTP Phosphohydrolases
Antigen-Antibody Complex
Actins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Maeda, K., Otomo, K., Yoshida, N., Abu-Asab, M. S., Ichinose, K., Nishino, T., ... Tsokos, G. C. (2018). CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease. Journal of Clinical Investigation, 128(8), 3445-3459. https://doi.org/10.1172/JCI99507

CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease. / Maeda, Kayaho; Otomo, Kotaro; Yoshida, Nobuya; Abu-Asab, Mones S.; Ichinose, Kunihiro; Nishino, Tomoya; Kono, Michihito; Ferretti, Andrew; Bhargava, Rhea; Maruyama, Shoichi; Bickerton, Sean; Fahmy, Tarek M.; Tsokos, Maria G.; Tsokos, George C.

In: Journal of Clinical Investigation, Vol. 128, No. 8, 01.08.2018, p. 3445-3459.

Research output: Contribution to journalArticle

Maeda, K, Otomo, K, Yoshida, N, Abu-Asab, MS, Ichinose, K, Nishino, T, Kono, M, Ferretti, A, Bhargava, R, Maruyama, S, Bickerton, S, Fahmy, TM, Tsokos, MG & Tsokos, GC 2018, 'CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease', Journal of Clinical Investigation, vol. 128, no. 8, pp. 3445-3459. https://doi.org/10.1172/JCI99507
Maeda, Kayaho ; Otomo, Kotaro ; Yoshida, Nobuya ; Abu-Asab, Mones S. ; Ichinose, Kunihiro ; Nishino, Tomoya ; Kono, Michihito ; Ferretti, Andrew ; Bhargava, Rhea ; Maruyama, Shoichi ; Bickerton, Sean ; Fahmy, Tarek M. ; Tsokos, Maria G. ; Tsokos, George C. / CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 8. pp. 3445-3459.
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