Human tissue kallikrein gene delivery attenuates hypertension, renal injury, and cardiac remodeling in chronic renal failure.
BACKGROUND
Tissue kallikrein cleaves kininogen substrate to produce the potent vasodilating peptide kinin, which plays important roles in cardiovascular and renal function. To explore cardiac and renal potential protective effects of kallikrein gene delivery in chronic renal failure, we delivered adenovirus carrying the human tissue kallikrein cDNA (cHK) into rats with 5/6 reduction of renal mass.


METHODS
Expression of human tissue kallikrein in rats was assessed by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR)/Southern blotting. Physiological parameters monitored in rats included systolic blood pressure, heart rate, and urinary excretion of protein, albumin, kinin, cGMP, cAMP, and nitrate/nitrites. Systemic and regional hemodynamics were measured by fluorescent-labeled microspheres. Heart weight and myocyte diameter were used to assess left ventricular hypertrophy. Quantitative and qualitative morphological analyses were used to evaluate histologic changes in kidney and heart sections.


RESULTS
Active tissue kallikrein reached a peak serum level of 463 +/- 76 ng/mL following gene delivery and returned to control levels within 21 days. A maximal blood pressure reduction of 37 mm Hg was observed within one week in rats receiving kallikrein gene delivery as compared with control rats receiving adenovirus containing the luciferase gene (159 +/- 5 vs. 196 +/- 6 mm Hg, N = 15, P < 0.001), and a significant blood pressure difference continued for five weeks postgene delivery. Kallikrein gene delivery significantly decreased total urinary protein and albumin excretion and increased levels of urinary kinin, nitrite/nitrate, and cGMP levels. Cardiac output and regional blood flow were also increased, while peripheral vascular resistance decreased. Kallikrein gene transfer reduced glomerular sclerotic lesions, tubular damage, lumenal protein cast accumulation, and interstitial inflammation in the kidney. Myocardial hypertrophy and fibrosis were also attenuated in rats receiving kallikrein gene delivery.


CONCLUSIONS
These findings indicated that kallikrein gene delivery attenuates hypertension and protects against renal injury and cardiac remodeling in the rat remnant kidney model of chronic renal failure.
Wolf
W C
WC
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425-2211, USA.
Yoshida
H
H
Agata
J
J
Chao
L
L
Chao
J
J
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001794:Blood Pressure; D001806:Blood Urea Nitrogen; D006332:Cardiomegaly / Q000473:pathology / Q000517:prevention & control; D006152:Cyclic GMP / Q000652:urine; D005355:Fibrosis / Q000517:prevention & control; D015870:Gene Expression / Q000502:physiology; D015316:Genetic Therapy; D006801:Humans; D006977:Hypertension, Renal / Q000473:pathology / Q000628:therapy*; D007275:Injections, Intravenous; D007676:Kidney Failure, Chronic / Q000473:pathology / Q000628:therapy*; D007705:Kinins / Q000652:urine; D008297:Male; D009392:Nephrectomy; D009566:Nitrates / Q000652:urine; D009573:Nitrites / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation; D020840:Tissue Kallikreins / Q000235:genetics*; D014655:Vascular Resistance; D014664:Vasodilation / Q000502:physiology; D020257:Ventricular Remodeling
D007705:Kinins; D009566:Nitrates; D009573:Nitrites; D020840:Tissue Kallikreins; D006152:Cyclic GMP