Biomedical subjects

J Chao

Publications and source records attributed to J Chao.

At least 55 records · Page 3Linked to original sources

PubMed1999

Adenovirus-mediated kallikrein gene delivery attenuates hypertension and protects against renal injury in deoxycorticosterone-salt rats.

To demonstrate potential therapeutic effects of kallikrein gene delivery in salt-induced hypertension and renal diseases, we delivered adenovirus carrying the human tissue kallikrein gene (Ad.CMV-cHK) into deoxycorticosterone acetate (DOCA)-salt hypertensive rats. A single intravenous injection of Ad.CMV-cHK caused a delay in the rise of blood pressure that began 2 days post gene delivery and lasted for more than 23 days. A maximal blood pressure reduction of 50 mm Hg was observed in rats receiving kallikrein gene delivery, as compared to rats receiving adenovirus containing the luciferase gene (Ad.CMV-Luc) (172 +/- 5 vs. 222 +/- 13 mm Hg, n = 6, P < 0.01). Throughout the experimental period, a blood pressure reduction of at least 32 mm Hg was observed in the DOCA-salt rats injected with Ad.CMV-cHK as compared to DOCA-salt rats receiving control adenovirus. Immunoreactive human tissue kallikrein levels were detected in rat serum and urine post gene delivery. Adenovirus-mediated kallikrein gene delivery caused a significant reduction in urinary excretion, urinary protein levels and body weight. Morphological examination of the kidney showed that kallikrein gene transfer significantly reduced DOCA-salt-induced glomerular sclerotic lesions, brush border disruption of proximal tubules, tubular dilatation and protein cast accumulation. These findings showed that the expression of human tissue kallikrein via gene delivery has protective effects against hypertension and renal injury in DOCA-salt hypertensive rats.

Adenoviridae↗

PubMed1999

Identification of pharmacokinetically stable 3, 10-dibromo-8-chlorobenzocycloheptapyridine farnesyl protein transferase inhibitors with potent enzyme and cellular activities.

Farnesyl protein transferase (FPT) is a promising target for the development of cancer chemotherapeutics because it is responsible for the farnesylation of oncogenic p21 Ras proteins which are found in nearly 30% of all human cancers and necessary for cellular development and growth. The recent discovery and progression to phase II clinical trials of trihalobenzocycloheptapyridine Sch-66336 as a potent inhibitor of FPT with oral, in vivo efficacy in mice have spawned extensive structure-activity relationship studies (SAR) of this class of compounds. Of the many trihalobenzocycloheptapyridine analogues prepared, we have identified several which inhibit FPT and cellular proliferation at single-digit nanomolar concentrations and which have good pharmacokinetic properties in mice.

Administration, Oral↗

PubMed1999

Specificity of human tissue kallikrein towards substrates containing Phe-Phe pair of amino acids.

We have explored in detail the determinants of specificity for the hydrolysis by human tissue kallikrein (hK1) of substrates containing the Phe-Phe amino acid pair, after which hK1 cleaves kallistatin (human kallikrein-binding protein), a specific serpin for this protease, as well as somatostatin 1-14. Internally quenched fluorogenic peptides were synthesized with the general structure Abz-peptidyl-EDDnp [Abz, o-aminobenzoic acid; EDDnp, N-(2, 4-dinitrophenyl)ethylenediamine], based on the natural reactive-centre loop sequence of kallistatin from P9 to P'13, and the kinetic parameters of their hydrolysis by hK1 were determined. All these peptides were cleaved after the Phe-Phe pair. For comparison, we have also examined peptides containing the reactive-centre loop sequences of human protein-C inhibitor (PCI) and rat kallikrein-binding protein, which were hydrolysed after Phe-Arg and Leu-Lys bonds, respectively. Hybrid peptides containing kallistatin-PCI sequences showed that the efficiency of hK1 activity on the peptides containing kallistatin and PCI sequences depended on both the nature of the P1 amino acid as well as on residues at the P- and P'-sides. Moreover, we have made systematic modifications on the hydrophobic pair Phe-Phe, and on Lys and Ile at the P3 and P4 positions according to the peptide substrate, Abz-AIKFFSRQ-EDDnp. All together, we concluded that tissue kallikrein was very effective on short substrates that are cleaved after the Phe-Arg pair; however, hydrolysis after Phe-Phe or other hydrophobic pairs of amino acids was more restrictive, requiring additional enzyme-substrate interaction and/or particular substrate conformations.

Amino Acid Sequence↗

PubMed1999

Immunohistochemical localization of kininogen in rat spinal cord and brain.

Kininogen localization has been determined by immunocytochemistry in rat spinal cord and brain using a kinin-directed kininogen monoclonal antibody. In the spinal cord, there were immunostained neurons and fibers in laminae I, II, VII, and IX, intensely stained fibers in the superficial layers of the dorsal horn, and immunoreactive glial and endothelial cells. Small neurons, satellite cells, and Schwann cells immunostained distinctly in the dorsal root ganglion. In the brain stem, there were immunoreactive neurons and fibers in the tractus solitarius and nucleus, trigeminal spinal tract and nuclei, periaqueductal gray matter, vestibular nuclei, cochlear nuclei, trapezoid body, medial geniculate nucleus, and red nucleus. Immunostained neurons and fibers were also found in cerebellum (dentate nucleus), cerebral cortex (layers III and V), hippocampus (pyramidal cell layer), and corpus callosum. Glia and endothelial cells stained in all brain regions. The widespread location of kininogen in neurons and their processes, as well as in glial and endothelial cells, indicates more than one functional role, including those proposed as a mediator, a calpain inhibitor, and a kinin precursor, in a variety of neural activities and responses.

Animals↗

PubMed1999

The bradykinin B1 receptor and the central regulation of blood pressure in spontaneously hypertensive rats.

1. We evaluated if the brain bradykinin (BK) B1 receptor is involved in the regulation of blood pressure (BP) in conscious rats. 2. Basal mean BP and HR were 115 +/- 2 and 165 +/- 3 mmHg and 345 +/- 10 and 410 +/- 14 beats min in Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR), respectively. Intracerebroventricular (i.c.v.) injection of 1 nmol B1 receptor agonist Lys-desArg9-BK significantly increased the BP of WKY and SHR by 7+/-1 and 19+/-2 mmHg, respectively. One nmol Sar[D-Phe8]-desArg9-BK, a kininase-resistant B1 agonist, increased the BP of WKY and SHR by 19+/-2 and 17+/-2 mmHg, respectively and reduced HR in both strains. 3. I.c.v. injection of 0.01 nmol B1 antagonists, LysLeu8-desArg9-BK or AcLys[D-betaNal7,Ile8]-desArg9-BK (R715), significantly decreased mean BP in SHR (by 9+/-2 mmHg the former and 14+/-3 mmHg the latter compound), but not in WKY. In SHR, the BP response to R715 was associated to tachycardia. 4. I.c.v. Captopril, a kininase inhibitor, increased the BP of SHR, this response being partially prevented by i.c.v. R715 and reversed into a vasodepressor effect by R715 in combination with the B2 antagonist Icatibant. 5. I.c.v. antisense oligodeoxynucleotides (ODNs) targeted to the B1 receptor mRNA decreased BP in SHR, but not in WKY. HR was not altered in either strain. Distribution of fluorescein-conjugated ODNs was detected in brain areas surrounding cerebral ventricles. 6. Our results indicate that the brain B1 receptor participates in the regulation of BP. Activation of the B1 receptor by kinin metabolites could participate in the pathogenesis of hypertension in SHR.

Adrenergic beta-Antagonists↗

PubMed1999

Atrial natriuretic peptide gene delivery attenuates gentamycin-induced nephrotoxicity in rats.

BACKGROUND: Atrial natriuretic peptide (ANP) is a cardiac hormone which exerts potent natriuretic and vasorelaxant activities. The aim of this study is to investigate potential protective effects of ANP gene delivery in gentamycin-induced nephrotoxicity. METHODS: Adenovirus (Ad.RSV-ANP) carrying the human ANP gene or carrying the LacZ gene (Ad.RSV-LacZ) under the control of the Rous sarcoma virus promoter were delivered intravenously on the first day of gentamycin administration. Sprague Dawley rats were injected subcutaneously with gentamycin daily for 10 days. RESULTS: A single systemic injection of Ad.RSV-ANP at a dose of 1.2x10(10) pfu results in a significant increase in urine excretion, water intake, urinary sodium and potassium excretion. Adenovirus-mediated ANP gene delivery significantly increased renal blood flow, glomerular filtration rates and urine flow as well as attenuated the elevation of blood urea nitrogen levels. Histological evaluations revealed that ANP delivery attenuated gentamycin-induced renal tubular damage, cellular necrosis, and lumenal protein casts. The expression of human ANP mRNA was identified in rat kidney, heart, aorta and liver. Immunoreactive human ANP was detected in the heart and kidney of rats injected with Ad.RSV-ANP but not in rats injected with Ad.RSV-LacZ. Cyclic GMP levels in the kidney were significantly increased in rats receiving ANP gene delivery. CONCLUSIONS: This study shows that ANP gene delivery exhibits protection against gentamycin-induced nephrotoxicity and raises the potential to use ANP gene therapy for the treatment of drug-induced renal failure.

Animals↗

PubMed1999

Kallikrein-binding protein is induced by growth hormone in the dwarf rat.

Rat kallikrein-binding protein (KBP), a member of the serpin family, is a tissue kallikrein inhibitor. It has been shown to be a potential pathogenic factor of diabetic retinopathy and may play a role in animal development and growth. To determine whether reduced KBP expression is involved in retarded animal growth, we examined the in vivo effect of growth hormone (GH) deficiency on the expression of KBP in the Lewis dwarf (dw/dw). We found that serum levels of functionally active KBP were reduced in the dwarf rat (P < 0.05) as determined by complex formation assay between serum KBP and (125)I-labeled rat tissue kallikrein. Enzyme-linked immunosorbent assay showed that KBP levels were significantly reduced in the serum of the dwarf rat compared to the Lewis rat (213.8 ng/ml vs. 413.8 ng/ml, n = 4, P < 0.01). The decreased KBP levels were confirmed by Western blot analysis. Moreover, treatment of the dwarf rat with recombinant human GH for 4 wk resulted in a significant increase in KBP activity (P < 0.01) and serum KBP levels compared with the untreated dwarf rat (549.8 ng/ml, n = 5, vs. 213.8 ng/ml, n = 4, P < 0.02). Northern blot analysis and densitometry showed that liver KBP mRNA levels were reduced by fivefold in the dwarf rat compared to the Lewis rat and the decrease was reversed by the GH treatment. These results indicate that the KBP levels are regulated at the RNA level. Furthermore, in vitro studies using cultured rat hepatocytes showed that GH may have a direct regulatory effect on KBP expression since KBP levels increased in the conditioned media of cells treated with GH. These results demonstrated that KBP is reduced in the genetic dwarf rat and is restored to normal by GH; therefore, KBP is a GH-dependent protein and may be a new target for studying the mechanism of pathological animal growth.

Animals↗

PubMed1999

Potassium supplement upregulates the expression of renal kallikrein and bradykinin B2 receptor in SHR.

High potassium intake is known to attenuate hypertension, glomerular lesion, ischemic damage, and stroke-associated death. Our recent studies showed that expression of recombinant kallikrein by somatic gene delivery reduced high blood pressure, cardiac hypertrophy, and renal injury in hypertensive animal models. The aim of this study is to explore the potential role of the tissue kallikrein-kinin system in blood pressure reduction and renal protection in spontaneously hypertensive rats (SHR) on a high-potassium diet. Young SHR were given drinking water with or without 1% potassium chloride for 6 wk. Systolic blood pressure was significantly reduced beginning at 1 wk, and the effect lasted for 6 wk in the potassium-supplemented group compared with that in the control group. Potassium supplement induced 70 and 40% increases in urinary kallikrein levels and renal bradykinin B2 receptor density, respectively (P < 0.05), but did not change serum kininogen levels. Similarly, Northern blot analysis showed that renal kallikrein mRNA levels increased 2.7-fold, whereas hepatic kininogen mRNA levels remained unchanged in rats with high potassium intake. No difference was observed in beta-actin mRNA levels in the kidney or liver of either group. Competitive RT-PCR showed a 1.7-fold increase in renal bradykinin B2 receptor mRNA levels in rats with high potassium intake. Potassium supplement significantly increased water intake, urine excretion, urinary kinin, cAMP, and cGMP levels. This study suggests that upregulation of the tissue kallikrein-kinin system may be attributed, in part, to blood pressure-lowering and diuretic effects of high potassium intake.

Animals↗

PubMed1999

Atrial natriuretic peptide gene delivery reduces stroke-induced mortality rate in Dahl salt-sensitive rats.

Atrial natriuretic peptide (ANP) is a powerful hormone with hypotensive, natriuretic, diuretic, and many other beneficial effects. Direct infusion of ANP in therapeutics has limited success because of its short half-life in the circulation. Our previous studies have shown that ANP gene delivery attenuates hypertension, cardiac hypertrophy, and renal injury in Dahl salt-sensitive (Dahl-SS) rats. To investigate the potential therapeutic value of ANP gene delivery on salt-induced stroke and cerebrovascular disorders, an adenovirus harboring the human ANP gene (Ad.RSV-cANP) was injected into Dahl-SS rats on a high salt diet. A single intravenous injection of the ANP gene caused a significant reduction of blood pressure that lasted for more than 3 weeks. A maximal blood pressure reduction of 28 mm Hg was observed 2 weeks after gene delivery as compared with that of control rats injected with adenovirus harboring the LacZ gene under the control of the Rous sarcoma virus promoter (Ad.RSV-LacZ). Immunoreactive human ANP can be detected in the heart, lung, kidney, and brain of rats after gene delivery. The stroke mortality rate of Dahl-SS rats was significantly decreased (from 54% to 17% at 3 weeks and from 70% to 50% at 4 weeks after ANP gene delivery as compared with rats injected with control virus). ANP gene delivery also significantly attenuates salt-induced aortic hypertrophy as evidenced by reduced thickness of the aortic wall. This is the first study to demonstrate the potential of ANP gene delivery in reducing the mortality rate caused by cerebrovascular disorders and stroke. Successful application of this technology may have potential value in treating individuals with a high risk of stroke.

Adenoviridae↗

PubMed1999

Kallikrein gene delivery inhibits vascular smooth muscle cell growth and neointima formation in the rat artery after balloon angioplasty.

Tissue kallikrein cleaves kininogen substrate to produce vasoactive kinin peptides that have been implicated in the proliferation of vascular smooth muscle cells (VSMCs). To explore potential roles of the kallikrein-kinin system in vascular biology, we evaluated the effects of adenovirus-mediated human kallikrein gene delivery on the growth of primary cultured VSMCs and in balloon-injured rat artery in vivo. Kallikrein gene transfer into cultured rat VSMCs resulted in time-dependent secretion of recombinant human tissue kallikrein and inhibition of cell proliferation. Balloon angioplasty reduced endogenous rat tissue kallikrein mRNA and protein levels at the injured site. In rats that received adenovirus-mediated human kallikrein gene delivery, we observed a 39% reduction in intima/media ratio at the injured vessel after delivery compared with that of rats that received control virus (n=8, P<0.01). Icatibant, a specific bradykinin B(2) receptor antagonist, blocked the protective effect and reversed the intima/media ratio to that of the control rats (n=5, P<0.01). After gene delivery, human kallikrein mRNA was identified at the injured vessel and a 3-fold increase occurred in kininogenase activity. cAMP and cGMP levels in balloon-injured aorta increased significantly at 4, 7, and 14 days after kallikrein gene delivery, but icatibant abolished the increase. These results provide new insights into the role of the vascular kallikrein-kinin system and have significant implications for gene therapy to treat restenosis or atherosclerosis.

Angioplasty, Balloon↗

PubMed1999

Adenovirus-mediated kallikrein gene delivery reduces aortic thickening and stroke-induced death rate in Dahl salt-sensitive rats.

BACKGROUND AND PURPOSE: Kallikrein gene delivery has been shown to attenuate hypertension, cardiac hypertrophy, and renal injury in hypertensive animal models. The aim of this study was to investigate the potential protective effects of kallikrein gene delivery in salt-induced stroke and cerebrovascular disorders. METHODS: Adenovirus harboring the human tissue kallikrein gene (AdCMV-cHK) was delivered intravenously into Dahl salt-sensitive (DS) rats after 4 weeks of high salt loading, and blood pressure was monitored weekly for 9 weeks. RESULTS: A single injection of AdCMV-cHK caused a significant reduction of systolic blood pressure compared with that in control rats, with or without an injection of adenovirus carrying the LacZ (control) gene (AdCMV-LacZ). A maximal blood pressure reduction of 21 mm Hg was observed 2 weeks after gene delivery. The stroke mortality rate of DS rats (AdCMV-LacZ group versus the AdCMV-cHK group) was significantly decreased: 38% versus 9% at 3 weeks and 54% versus 27% at 5 weeks after gene delivery. Kallikrein gene delivery significantly attenuated salt-induced aortic hypertrophy, as evidenced by reduced thickness of the aortic wall. Recombinant human tissue kallikrein was detected in rat serum and urine after gene transfer. Kinin-releasing activities in the brain as well as urinary kinin and cGMP levels were significantly increased in rats receiving the kallikrein gene. CONCLUSIONS: This is the first study to demonstrate the protective effect of kallikrein gene delivery in reducing salt-induced stroke mortality and vascular dysfunction.

Adenoviridae↗

PubMed1999

Localization and expression of tissue kallikrein and kallistatin in human blood vessels.

Tissue kallikrein releases kinins by specific proteolysis, an activity inhibited by kallistatin. In this study, kallikrein and kallistatin were localized to endothelial and smooth muscle cells of large, medium, and small normal blood vessels by immunohistochemical techniques. Immunostaining for both proteins was strong in the endothelium of all sizes of blood vessels and was more intense in medial smooth muscle cells of small and medium-sized blood vessels than in elastic arteries. The sites of synthesis by endothelial and smooth muscle cells were demonstrated in normal blood vessels of all sizes by in situ hybridization histochemistry. Kallikrein and kallistatin levels were measured by immunoassays in homogenates of human aorta, vena cava, and iliac artery and vein. Tissue kallikrein and kallistatin transcripts were identified in human blood vessels by RT-PCR followed by Southern blot analysis with specific oligonucleotide probes. The results demonstrated the expression and co-localization of tissue kallikrein and kallistatin in human vessels and suggest a potential role of kallistatin in regulating tissue kallikrein in blood vessels.

Blood Vessels↗

PubMed1999

Human tissue kallikrein attenuates hypertension and secretes into circulation and urine after intramuscular gene delivery in hypertensive rats.

Systemic delivery of the human tissue kallikrein transgene has been shown to markedly delay the increase of blood pressure in hypertensive rat models. To demonstrate potential hypotensive effects of kallikrein via local delivery, adenovirus carrying the human tissue kallikrein gene was inoculated into quadriceps of spontaneously hypertensive rats (SHR). A single intramuscular injection of the kallikrein gene caused a significant delay of blood pressure increase for 5 weeks. The expression of human tissue kallikrein and its mRNA was identified solely in injected muscle. Immunoreactive human tissue kallikrein was detected in the muscle as well as in the circulation and urine of adult and newborn rats. Urinary kinin and cGMP levels increased significantly in rats receiving kallikrein gene delivery as compared with rats receiving control virus containing the LacZ gene. The detection of human tissue kallikrein in rat urine after local gene delivery into the muscle provides direct evidence that circulatory kallikrein can be secreted into the urine. These findings indicated that a continuous supply of human tissue kallikrein in the circulation is sufficient to reduce blood pressure and kallikrein gene delivery via the intramuscular route may have significant implications in therapeutic applications.

Adenoviridae↗

PubMed1998

Molecular cloning and expression of rat bradykinin B1 receptor.

The gene encoding rat bradykinin B1 receptor has been cloned by using a partial rat B1 cDNA probe. The rat B1 receptor gene contains two exons and the entire coding region is within the second exon. The 5'-flanking region of the rat B1 receptor gene contains several putative transcriptional regulatory sites including TATA box, cAMP response element, NF-kappaB and AP-1. It showed promoter activity inducible by lipopolysaccharide in vascular smooth muscle cells. Rat B1 receptor mRNA was found to be alternatively spliced and induced by lipopolysaccharide treatment in a wide range of tissues, such as the salivary gland, testis, kidney, lung, heart, prostate and aorta. The deduced rat B1 receptor amino acid sequence is 71% homologous to human and rabbit counterparts, and 89% homologous to the mouse counterpart. The expressed B1 receptor in HEK293 cells displayed a rank order of affinity for the kinin peptides: des-Arg9-BK>Lys-des-Arg9-BK approximately des-Arg9, Leu8-BK>Sar-Tyr-epsilonAhx-Lys-[D-betaNal7, Ile8]-des-Arg9-BK>Sar-Tyr-epsilonAhx-Lys-des-Arg9-BK>>BK>> Hoe140. These results indicate that the cloned gene encodes a functional rat B1 receptor.

Amino Acid Sequence↗

PubMed1998

Atrial natriuretic peptide gene delivery attenuates hypertension, cardiac hypertrophy, and renal injury in salt-sensitive rats.

To investigate potential therapeutic effects of atrial natriuretic peptide (ANP) gene delivery on renal and cardiac disorders, adenovirus harboring the human ANP gene (Ad.RSV-cANP) was delivered into Dahl salt-sensitive (DSS) rats on a high-salt diet. A single intravenous injection of the ANP gene caused a significant delay of blood pressure increase 3 days post-injection and the effect lasted for more than 5 weeks. A maximal blood pressure reduction of 32.8 mmHg was observed after ANP gene delivery, as compared with that of control rats injected with Ad.CMV-LacZ. Immunoreactive human ANP can be detected in the heart, lung, and kidney of rats after gene delivery. ANP gene delivery caused significant increases in renal blood flow, glomerular filtration rate, sodium output, urine excretion, and urinary cGMP levels. These beneficial effects were reflected morphologically by a reduction in cardiomyocyte size, attenuation of the glomerular-sclerotic lesions, tubular injury and arterial thickening. This study demonstrated the usefulness of somatic gene transfer as a new tool for ANP gene delivery in studying salt-related hypertension and renal and cardiovascular diseases. In addition, the findings also suggest that ANP gene delivery may have potential in therapeutic applications.

Adenoviridae↗

PubMed1998

Central delivery of human tissue kallikrein gene reduces blood pressure in hypertensive rats.

The human tissue kallikrein gene, in the form of naked DNA (CMV-cHK) or an adenoviral vector (Ad.CMV-cHK), was directly delivered by intracerebroventricular injection into spontaneously hypertensive rats. Control rats received the same amount of vector DNA (pcDNA3) or adenoviral vector (Ad.CMV-LacZ) carrying the lacZ gene. A single injection of the human tissue kallikrein gene caused a rapid and prolonged blood pressure-lowering effect that began 1 day post injection and the effect lasted for more than 7 days. The expression of human tissue kallikrein and its mRNA was identified in the cortex, cerebellum, brain stem, hippocampus and hypothalamus. Cellular localization of beta-galactosidase was detected by X-gal staining in the thalamus, hypothalamus and third ventricle in rats injected with Ad.CMV-LacZ. This suggests that the tissue kallikrein-kinin system may function in the central control of blood pressure homeostasis.

Adenoviridae↗

PubMed1998

Transcription factor nuclear factor kappaB regulates the inducible expression of the human B1 receptor gene in inflammation.

Expression of the bradykinin B1 receptor gene is up-regulated in vascular smooth muscle cells (VSMCs) in response to a variety of inflammatory stimuli. We isolated the 5'-flanking region of the human bradykinin B1 receptor gene and examined its promoter activity by transient transfection analysis. This region (-2582 to +34) showed promoter activity inducible by lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF-alpha), and interleukin-1beta (IL-1beta) in VSMCs. Further deletion analysis revealed that constructs containing 111 base pairs of 5'-flanking sequence were sufficient for transcriptional induction. Mutagenesis of a nuclear factor kappaB (NF-kappaB)-like site at -64 to -55 abolished most of the LPS, TNF-alpha, and IL-1beta inducibility, whereas a mutation of a cyclic AMP response element at -50 to -43 markedly reduced the basal promoter activity, and a mutation of the activator protein 1 (AP-1) site at -78 to -72 had minimal effects. Nuclear extracts from LPS, TNF-alpha, and IL-1beta-treated VSMCs, IL-1beta-treated human hepatoma HepG2, and human lung fibroblast IMR-90 cells showed strong inducible binding activity to the NF-kappaB-like site by gel shift assays. These results demonstrated that NF-kappaB-like nuclear factor was involved in the inducible expression of the human bradykinin B1 receptor gene during inflammatory processes.

Amino Acid Sequence↗

PubMed1998

Human kallikrein gene delivery attenuates hypertension, cardiac hypertrophy, and renal injury in Dahl salt-sensitive rats.

The tissue kallikrein-kinin system has been documented to be involved in the pathogenesis of hypertension and renal diseases. To investigate the protective effects of kallikrein gene delivery on salt-induced renal damage, cardiac dysfunction, and hypertension, adenovirus harboring the human tissue kallikrein gene under the control of the cytomegalovirus promoter Ad.CMV-cHK was delivered into Dahl salt-sensitive (Dahl-SS) rats fed to a high-salt (4% NaCl) diet. A single intravenous injection of Ad.CMV-cHK resulted in a significant reduction of blood pressure beginning 2 days post injection and the effect lasted for 4 weeks. The human kallikrein mRNA was detected in rat heart, kidney, lung, liver, and adrenal gland; immunoreactive human kallikrein can be measured in the liver, kidney, sera, and urine of rats receiving kallikrein gene delivery. Following Ad.CMV-cHK injection, a significant increase in urine excretion, urinary sodium output, kinin, and cGMP level was observed. Kallikrein gene delivery caused a significant reduction in the left ventricular mass and cardiomyocyte size as well as inhibition of glomerular sclerotic lesions and tubular dilatation. This study shows that adenovirus-mediated gene delivery in Dahl-SS rats fed a high-salt diet resulted in (i) prolonged reduction of blood pressure and increased urinary kinin and cGMP levels, consistent with blood pressure reductions mediated via kinin through a cGMP-dependent signal transduction pathway, (ii) inhibition of cardiac hypertrophy, and (iii) attenuation of renal injury. The ability of kallikrein gene transfer to produce a wide spectrum of beneficial effects makes it an excellent candidate in treating salt-related hypertension as well as cardiovascular and renal diseases.

Adenoviridae↗