Calcium/Calmodulin Kinase IV Controls the Function of Both T Cells and Kidney Resident Cells

Abstract

Calcium calmodulin kinase IV (CaMK4) regulates multiple processes that significantly contribute to the lupus-related pathology by controlling the production of IL-2 and IL-17 by T cells, the proliferation of mesangial cells, and the function and structure of podocytes. CaMK4 is also upregulated in podocytes from patients with focal segmental glomerulosclerosis (FSGS). In both immune and non-immune podocytopathies, CaMK4 disrupts the structure and function of podocytes. In lupus-prone mice, targeted delivery of a CaMK4 inhibitor to CD4⁺ T cells suppresses both autoimmunity and the development of nephritis. Targeted delivery though to podocytes averts the deposition of immune complexes without affecting autoimmunity in lupus-prone mice and averts pathology induced by adriamycin in normal mice. Therefore, targeted delivery of a CaMK4 inhibitor to podocytes holds high therapeutic promise for both immune (lupus nephritis) and non-immune (FSGS) podocytopathies.

Keywords: CaMK4; IL-17; IL-2 deprivation; Treg deficiency; calcium/calmodulin kinase IV; podocyte dysfunction.

Figure 1

Overactive CaMK4 in T cells signals to reduce IL-2 and increase IL-17 production. In patients with SLE, FcRγ, instead of CD3ζ, associates with the TCR complex and signals through Syk generating a stronger calcium signal. Overactive CaMK4 phosphorylates CREMα and mitigates IL-2 transcription. Concomitantly, CaMK4 promotes IL-17 production through activation of RORγt by phosphorylating AKT.

Figure 2

CaMK4 contributes to podocyte dysfunction in autoimmune and non-autoimmune kidney disease. Multiple stimuli including IgG from SLE patients or LPS upregulate CaMK4 leading to destabilization of the actin network and downregulation of nephrin and podocin. TRPC5, short transient receptor potential channel 5.