PMID- 23676587
OWN - NLM
STAT- MEDLINE
DCOM- 20140103
LR  - 20190606
IS  - 1349-7235 (Electronic)
IS  - 0918-2918 (Linking)
VI  - 52
IP  - 10
DP  - 2013
TI  - Inhibition of calcium(2+)/calmodulin-dependent protein kinase type IV ameliorates 
      experimental nephrotic syndrome.
PG  - 1035-41
AB  - 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 
      (alpha-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). CONCLUSION: 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.
FAU - Ao, Qiangguo
AU  - Ao Q
AD  - Department of Geriatric Nephrology, Institute of Gerontology, Chinese PLA General 
      Hospital, China.
FAU - Cheng, Qingli
AU  - Cheng Q
FAU - Ma, Qiang
AU  - Ma Q
FAU - Wang, Xiaodan
AU  - Wang X
FAU - Liu, Sheng
AU  - Liu S
LA  - eng
PT  - Journal Article
DEP - 20130515
PL  - Japan
TA  - Intern Med
JT  - Internal medicine (Tokyo, Japan)
JID - 9204241
RN  - 0 (Acta2 protein, mouse)
RN  - 0 (Actins)
RN  - 0 (Benzylamines)
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Cytokines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Sulfonamides)
RN  - 0 (Transforming Growth Factor beta)
RN  - 139298-40-1 (KN 93)
RN  - 80168379AG (Doxorubicin)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 4)
SB  - IM
MH  - Actins/biosynthesis/genetics
MH  - Animals
MH  - Benzylamines/pharmacology/*therapeutic use
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 4/*antagonists & 
      inhibitors/biosynthesis/genetics/physiology
MH  - Chemokine CCL2/biosynthesis/genetics
MH  - Cytokines/metabolism
MH  - Disease Models, Animal
MH  - Doxorubicin/toxicity
MH  - Drug Evaluation, Preclinical
MH  - Enzyme Induction/drug effects
MH  - Glomerulosclerosis, Focal Segmental/chemically induced/complications
MH  - Kidney/drug effects/metabolism/pathology
MH  - Macrophages/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Nephritis, Interstitial/chemically induced/complications
MH  - Nephrotic Syndrome/chemically induced/*drug 
      therapy/enzymology/metabolism/pathology
MH  - Protein Kinase Inhibitors/pharmacology/*therapeutic use
MH  - Proteinuria/etiology/prevention & control
MH  - Sulfonamides/pharmacology/*therapeutic use
MH  - T-Lymphocytes/pathology
MH  - Transforming Growth Factor beta/biosynthesis/genetics
MH  - Up-Regulation/drug effects
EDAT- 2013/05/17 06:00
MHDA- 2014/01/05 06:00
CRDT- 2013/05/17 06:00
PHST- 2013/05/17 06:00 [entrez]
PHST- 2013/05/17 06:00 [pubmed]
PHST- 2014/01/05 06:00 [medline]
AID - DN/JST.JSTAGE/internalmedicine/52.9574 [pii]
AID - 10.2169/internalmedicine.52.9574 [doi]
PST - ppublish
SO  - Intern Med. 2013;52(10):1035-41. doi: 10.2169/internalmedicine.52.9574. Epub 2013 
      May 15.