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
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
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Research Article Autoimmunity Nephrology

CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease

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

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Figure 5

Podocyte-targeted delivery of KN93 prevents and reverses adriamycin-induced podocyte injury in mice.

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Podocyte-targeted delivery of KN93 prevents and reverses adriamycin-indu...
Each mouse was injected i.v. with adriamycin (ADM) on day 0. (A–C) Anti-nephrin antibody–coated empty or KN93-loaded nlg were injected i.p. into BALB/c mice on day –1 and day 3 (n = 7 in each group). (A) Mean urine albumin/creatinine ratio from mice subjected to the indicated treatment. Error bars represent mean ± SEM. ****P < 0.0001, 2-way ANOVA with Bonferroni’s post test (B) Representative images showing PAS staining of kidney from BALB/c mice treated with anti-nephrin antibody–coated empty nlg or KN93-loaded nlg. Scale bar: 50 μm. (C) Representative immunofluorescence images of nephrin and synaptopodin expression in glomeruli. Scale bar: 100 μm. (D) Free KN93 (10 μg/wk), anti-nephrin antibody–coated empty, or KN93-loaded nlg (10 μg of KN93/wk) were injected i.p. into BALB/c mice on day 7 (n = 5 in each group). **P < 0.01; ***P < 0.001, 2-way ANOVA with Bonferroni’s post test. (E) Mean urine albumin/creatinine ratio of B6 or B6 Camk4–/– mice treated with adriamycin. (n = 5 in each group; 2 independent experiments were performed). ****P < 0.0001, 2-way ANOVA with Bonferroni’s post-test. (F) Representative electron microscopy images of glomeruli from BALB/c mice at 7 days after exposure to adriamycin, treated with anti-nephrin antibody–coated empty nlg (left) or KN93-loaded nlg (right). Original magnification, ×8,000.