Biomaterial Database

CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease. 2018

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

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

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.

UI	MeSH Term	Description	Entries
D007678	Kidney Glomerulus	A cluster of convoluted capillaries beginning at each nephric tubule in the kidney and held together by connective tissue.	Glomerulus, Kidney
D008181	Lupus Nephritis	Glomerulonephritis associated with autoimmune disease SYSTEMIC LUPUS ERYTHEMATOSUS. Lupus nephritis is histologically classified into 6 classes: class I - normal glomeruli, class II - pure mesangial alterations, class III - focal segmental glomerulonephritis, class IV - diffuse glomerulonephritis, class V - diffuse membranous glomerulonephritis, and class VI - advanced sclerosing glomerulonephritis (The World Health Organization classification 1982).	Glomerulonephritis, Lupus,Lupus Glomerulonephritis,Nephritis, Lupus,Glomerulonephritides, Lupus,Lupus Glomerulonephritides,Lupus Nephritides,Nephritides, Lupus
D008297	Male		Males
D008807	Mice, Inbred BALB C	An inbred strain of mouse that is widely used in IMMUNOLOGY studies and cancer research.	BALB C Mice, Inbred,BALB C Mouse, Inbred,Inbred BALB C Mice,Inbred BALB C Mouse,Mice, BALB C,Mouse, BALB C,Mouse, Inbred BALB C,BALB C Mice,BALB C Mouse
D011507	Proteinuria	The presence of proteins in the urine, an indicator of KIDNEY DISEASES.	Proteinurias
D002461	Cell Line, Transformed	Eukaryotic cell line obtained in a quiescent or stationary phase which undergoes conversion to a state of unregulated growth in culture, resembling an in vitro tumor. It occurs spontaneously or through interaction with viruses, oncogenes, radiation, or drugs/chemicals.	Transformed Cell Line,Cell Lines, Transformed,Transformed Cell Lines
D005260	Female		Females
D005923	Glomerulosclerosis, Focal Segmental	A clinicopathological syndrome or diagnostic term for a type of glomerular injury that has multiple causes, primary or secondary. Clinical features include PROTEINURIA, reduced GLOMERULAR FILTRATION RATE, and EDEMA. Kidney biopsy initially indicates focal segmental glomerular consolidation (hyalinosis) or scarring which can progress to globally sclerotic glomeruli leading to eventual KIDNEY FAILURE.	Glomerulonephritis, Focal Sclerosing,Hyalinosis, Segmental Glomerular,Focal Segmental Glomerulosclerosis,Glomerulosclerosis, Focal,Hyalinosis, Segmental,Segmental Glomerular Hyalinosis,Focal Glomerulosclerosis,Focal Sclerosing Glomerulonephritides,Focal Sclerosing Glomerulonephritis,Glomerular Hyalinosis, Segmental,Glomerulonephritides, Focal Sclerosing,Sclerosing Glomerulonephritides, Focal,Sclerosing Glomerulonephritis, Focal,Segmental Glomerulosclerosis, Focal,Segmental Hyalinosis
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia