title: Inhibition of calcium(2+)/calmodulin-dependent protein kinase type IV ameliorates experimental nephrotic syndrome.
abstract: OBJECTIVE
  Evidence has demonstrated that Ca(2+)/calmodulin-dependent protein kinase type IV (CaMKIV) contributes to altered cytokine production by promoting the production of inflammatory cytokines. This study aimed to explore the protective role and underlying mechanisms of CaMKIV inhibition in experimental nephrotic syndrome.
  
  
  METHODS
  BALB/c mice received single intravenous injections of adriamycin (10 mg/kg) then were sacrificed at two, four and six weeks. In the second study, treatment with KN-93, a CaMKIV inhibitor, or vehicle administered via intraperitoneal injection was started five days after adriamycin injection. Functional and pathologic parameters, the presence of inflammatory infiltration and the expressions of pro-inflammatory cytokines were assessed.
  
  
  RESULTS
  The CaMKIV protein expression levels were upregulated in the mice with adriamycin nephropathy, which was significantly inhibited by KN-93 (p<0.01). As compared with the vehicle-treated controls, KN-93 treatment resulted in marked suppression of proteinuria and serum creatinine at week 6 (p<0.01), but not at two weeks after induction of the disease. KN-93 inhibited glomerulosclerosis and the development of tubulointerstitial lesions. The renal alpha-smooth muscle actin (α-SMA) expression was also significantly suppressed by KN-93 treatment at week 6 (p<0.01). Moreover, KN-93 inhibited the renal monocyte chemoattractant protein-1 (MCP-1) expression, paralleled by a reduction in the interstitial infiltration of macrophages and T-cells (p<0.01).
  
  
  CONCLUSIONS
  Our findings suggest that activation of CaMKIV signaling is involved in the progression of glomerular diseases with a proteinuric state. Our data therefore justify the development of small molecule CaMKIV inhibitors for the treatment of clinical nephrotic syndrome.
authors.affiliation: Department of Geriatric Nephrology, Institute of Gerontology, Chinese PLA General Hospital, China.
authors.forename: Qiangguo
authors.initials: Q
authors.lastname: Ao
authors.forename: Qingli
authors.initials: Q
authors.lastname: Cheng
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ma
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Wang
authors.forename: Sheng
authors.initials: S
authors.lastname: Liu
mesh_terms: D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology / Q000627:therapeutic use*; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D004790:Enzyme Induction / Q000187:drug effects; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000150:complications; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000150:complications; D009404:Nephrotic Syndrome / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011507:Proteinuria / Q000209:etiology / Q000517:prevention & control; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects; D000096926:Benzenesulfonamides
chemical_list: D000199:Actins; D001596:Benzylamines; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D018932:Chemokine CCL2; D016207:Cytokines; D004317:Doxorubicin; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D016212:Transforming Growth Factor beta; C558396:Acta2 protein, mouse; C491768:Ccl2 protein, mouse; C072105:KN 93; D000096926:Benzenesulfonamides