Calcium calmodulin kinase IV deficiency in podocytes prevents the development of lupus nephritis

Abstract

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by widespread organ involvement including the kidney. Calcium/calmodulin-dependent protein kinase IV (CaMK4) has been shown to conrol immune cell nad podocyte function. To address the effect of genetic podocyte-specific CaMK4 deficiency on systemic autoimmunity and kidney pathology in lupus-prone mice we generated B6.lpr.Camk4 ^flox.^.podocin^cre mice. Although podocyte-specific CaMK4 deletion in the lupus-prone Br.lpr mice did not affect systemic autoimmune response parameters, it led to significant improvement of kidney pathology and clinical outcomes. Specifically, B6.lpr.Camk4 ^flox.^.podocin^cre mice exhibited reduced glomerular pathology, characterized by less mesangial cell proliferation and diminished immune complex deposition, accompanied by decreased levels of albuminuria and improved creatinine levels. CaMK4 deficiency in podocytes averted the deposition of immune complexes in the kidney. Interestingly, we found increased deposition of immune complexes in the liver. We conclude that CaMK4 expression in podocytes is central to the development of LN and its targeted deletion in podocytes prevents its development without affecting systemic autoimmunity while immune complexes appear to be re-directed from the kidney to the liver.