title: Kallikrein gene transfer reduces renal fibrosis, hypertrophy, and proliferation in DOCA-salt hypertensive rats.
abstract: In DOCA-salt hypertension, renal kallikrein levels are increased and may play a protective role in renal injury. We investigated the effect of enhanced kallikrein levels on kidney remodeling of DOCA-salt hypertensive rats by systemic delivery of adenovirus containing human tissue kallikrein gene. Recombinant human kallikrein was detected in the urine and serum of rats after gene delivery. Kallikrein gene transfer significantly decreased DOCA- and salt-induced proteinuria, glomerular sclerosis, tubular dilatation, and luminal protein casts. Sirius red staining showed that kallikrein gene transfer reduced renal fibrosis, which was confirmed by decreased collagen I and fibronectin levels. Furthermore, kallikrein gene delivery diminished myofibroblast accumulation in the interstitium of the cortex and medulla, as well as transforming growth factor (TGF)-beta1 immunostaining in glomeruli. Western blot analysis and ELISA verified the decrease in immunoreactive TGF-beta1 levels. Kallikrein gene transfer also significantly reduced kidney weight, glomerular size, proliferating tubular epithelial cells, and macrophages/monocytes. Reduction of proliferation and hypertrophy was associated with reduced levels of the cyclin-dependent kinase inhibitor p27(Kip1), and the phosphorylation of c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). The protective effects of kallikrein were accompanied by increased urinary nitrate/nitrite and cGMP levels, and suppression of superoxide formation. These results indicate that kallikrein protects against mineralocorticoid-induced renal fibrosis glomerular hypertrophy, and renal cell proliferation via inhibition of oxidative stress, JNK/ERK activation, and p27(Kip1) and TGF-beta1 expression.
authors.affiliation: Dept. of Biochemistry and Molecular Biology, Medical Univ. of South Carolina, 173 Ashley Ave., PO Box 250509, Charleston, SC 29425, USA.
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Xia
authors.forename: Grant
authors.initials: G
authors.lastname: Bledsoe
authors.forename: Lee
authors.initials: L
authors.lastname: Chao
authors.forename: Julie
authors.initials: J
authors.lastname: Chao
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division; D006152:Cyclic GMP / Q000652:urine; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003900:Desoxycorticosterone / Q000494:pharmacology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005355:Fibrosis; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D006977:Hypertension, Renal / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006984:Hypertrophy; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007610:Kallikreins / Q000235:genetics*; D008297:Male; D009566:Nitrates / Q000652:urine; D018384:Oxidative Stress; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017673:Sodium Chloride, Dietary / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D009566:Nitrates; D017673:Sodium Chloride, Dietary; C508960:TGFB1 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D003900:Desoxycorticosterone; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D007610:Kallikreins; D006152:Cyclic GMP