Delivery of recombinant adeno-associated virus-mediated human tissue kallikrein for therapy of chronic renal failure in rats.
The tissue kallikrein-kinin system is important in regulating cardiovascular and renal function, and dysregulation of the system has been implicated in heart and kidney pathologies. These findings suggest that if balance can be restored to the kallikrein-kinin axis, then associated disease progression may be attenuated. To test this hypothesis, recombinant adeno-associated virus (rAAV)-mediated human tissue kallikrein (HK) expression was induced in a rodent model of chronic renal failure involving 5/6 nephrectomy (nephrectomy plus 70% reduction of remaining kidney). rAAV-HK treatment attenuated the rise in blood pressure, glomerular sclerosis, and tubulointerstitial injury observed in this model. rAAV-HK treatment also attenuated renal function decline as measured by urinary microalbumin, osmolarity, and cGMP levels. Reverse transcriptase-polymerase chain reaction analysis showed that rAAV-HK-treated rats had higher levels of bradykinin receptor-2 (B(2)R) and dopamine receptor-1 mRNAs. In contrast, angiotensin II receptor-1, endothelin receptor-A, and vasopressin receptor-2 mRNAs were markedly downregulated in kidneys from HK-treated rats. Bradykinin induced similar changes in receptor levels and prevented transforming growth factor-beta(1)-induced tubulointerstitial fibrosis. The effects of bradykinin could be reversed with the B(2)R antagonist HOE-140. Together, these findings suggest that restoration of the kallikrein-kinin system reduces kidney injury and protects renal function in 5/6-nephrectomized rats via changes in the expression and activation of G protein-coupled receptors including B(2)R.
Tu
Ling
L
Institute of Hypertension and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Xu
Xizhen
X
Wan
Huaibing
H
Zhou
Changqing
C
Deng
Juanjuan
J
Xu
Gang
G
Xiao
Xiao
X
Chen
Yipu
Y
Edin
Matthew L
ML
Voltz
James W
JW
Zeldin
Darryl C
DC
Wang
Dao Wen
DW
D000419:Albuminuria; D000818:Animals; D001794:Blood Pressure; D001920:Bradykinin / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D006152:Cyclic GMP / Q000652:urine; D000229:Dependovirus / Q000235:genetics*; D015316:Genetic Therapy; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000628:therapy*; D008297:Male; D023421:Models, Animal; D009392:Nephrectomy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D015398:Signal Transduction; D020840:Tissue Kallikreins / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; D003404:Creatinine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020840:Tissue Kallikreins; D006152:Cyclic GMP; D001920:Bradykinin