BACKGROUND/AIMS: There has been controversy about the role of Toll-like receptor 2 (TLR2) in renal injury following ureteric obstruction. Although inhibition of the renin angiotensin system (RAS) reduces TLR2 expression in mice, the exact relationship between TLR2 and RAS is not known. The aim of this study was to determine whether the RAS modulates TLR2. METHODS: We used 8-week-old male wild type (WT) and TLR2-knockout (KO) mice on a C57Bl/6 background. Unilateral ureteral obstruction (UUO) was induced by complete ligation of the left ureter. Angiotensin (Ang) II (1,000 ng/kg/min) and the direct renin inhibitor aliskiren (25 mg/kg/day) were administrated to mice using an osmotic minipump. Molecular and histologic evaluations were performed. RESULTS: Ang II infusion increased mRNA expression of TLR2 in WT mouse kidneys (p < 0.05). The expression of renin mRNA in TLR2-KO UUO kidneys was significantly higher than that in WT UUO kidneys (p < 0.05). There were no differences in tissue injury score or mRNA expression of monocyte chemotactic protein 1 (MCP-1), osteopontin (OPN), or transforming growth factor beta (TGF-beta) between TLR2-KO UUO and WT UUO kidneys. However, aliskiren decreased the tissue injury score and mRNA expression of TLR2, MCP-1, OPN, and TGF-beta in WT UUO kidneys (p < 0.05). Aliskiren-treated TLR2-KO UUO kidneys showed less kidney injury than aliskiren-treated WT UUO kidneys. CONCLUSIONS: TLR2 deletion induced activation of the RAS in UUO kidneys. Moreover, inhibition of both RAS and TLR2 had an additive ameliorative effect on UUO injury of the kidney.
Amides/*pharmacology ; Angiotensin II/pharmacology ; Animals ; Disease Models, Animal ; Fibrosis ; Fumarates/*pharmacology ; Kidney/*drug effects/metabolism/pathology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Nephritis, Interstitial/genetics/metabolism/pathology/*prevention & control ; RNA, Messenger/genetics/metabolism ; Renin/*antagonists & inhibitors/metabolism ; Renin-Angiotensin System/*drug effects ; Toll-Like Receptor 2/deficiency/drug effects/genetics/*metabolism ; Ureteral Obstruction/*drug therapy/genetics/metabolism/pathology

OBJECTIVES: Spontaneously hypertensive rats (SHR) are frequently used as rat models of essential hypertension. The mechanism for the development of hypertension is complicated and it is unknown. The renin-angiotensin system (RAS) plays a key role in the control of blood pressure. Microarrays are a powerful tool for studying genetics. The purpose of this study was to investigate changes of gene expression in the heart tissues of SHR after losartan treatment to provide basic data that is useful in the early diagnosis of hypertension and gene treatment. METHODS: Rats were divided into three groups: the control (C) group; the hypertension (H) group (SHR), and the losartan (L) group; treated with losartan (10 mg/kg/day) in SHR. Rats were sacrificed at week 5 and microarray analysis was performed. RESULTS: 102 gene expressions including the genes associated with cell proliferation such as Raf1, Uchl1, Btla, Spock1 were increased. The other 139 gene expressions, including the genes related to the regulation of metabolism such as TFIID, Auf1, Bmp, Hub, Taf51 showed decreases in gene expression. A total of 31 genes were differentially expressed in the L group compared to the H group. Of these, 16 genes including the genes associated with macromolecule metabolism such as MGC105766, Ppp1r1a, Rpl3l showed increased expression. The other 15 genes including the genes associated with primary metabolism such as Mcpt4, Ngn3, Tdo, Ak2 Hyal2 showed decreased expressions. CONCLUSION: According to microarray analysis, there was significant gene expression change in SHR compared with normal rats as well as significant gene expression changes after losartan treatment in SHR.
Animals ; Blood Pressure ; Cell Proliferation ; Early Diagnosis ; Gene Expression ; Genetics ; Heart* ; Hypertension ; Losartan* ; Metabolism ; Microarray Analysis* ; Models, Animal ; Rats ; Rats, Inbred SHR* ; Renin-Angiotensin System ; Transcription Factor TFIID

PURPOSE: The aim of the present study was to investigate associations between the renin gene (REN) and the risk of essential hypertension and blood pressure (BP) levels in Koreans. MATERIALS AND METHODS: To outline the functional role of a single nucleotide polymorphism in the transcription of the REN gene, we conducted a case-control study of 1975 individuals: 646 hypertension (HT) patients and 1329 ethnically and age-matched normotensive subjects. RESULTS: Logistic regression analysis indicated that the genotypes AA/AG were strongly associated with risk of HT (odds ratio, 1.493; 95% confidence interval, 1.069-2.086, p=0.018) in female subjects. The genotypes AA/AG also showed significant association with higher blood pressure levels, both systolic and diastolic, in postmenopausal HT women (p=0.003 and p=0.017, respectively). Analysis of the promoter containing rs6682082 revealed a 2.4+/-0.01-fold higher activity in the A variant promoter than the G variant promoter, suggesting that rs6682082 is itself a functional variant. CONCLUSION: We suggest that the A allele of rs6682082 is a positive genetic marker for predisposition to essential hypertension and high BP in Korean women and may be mediated through the transcriptional activation of REN.
Alleles ; Asian Continental Ancestry Group/*genetics ; Blood Pressure/*genetics ; Case-Control Studies ; Diastole/genetics ; Female ; Gene Frequency ; *Genetic Association Studies ; *Genetic Predisposition to Disease ; Humans ; Hypertension/*genetics/*physiopathology ; Luciferases/metabolism ; Middle Aged ; Polymorphism, Single Nucleotide/*genetics ; Promoter Regions, Genetic/genetics ; Renin/*genetics ; Republic of Korea ; Risk Factors ; Systole/genetics ; Transfection

Aging is associated with progressive functional deterioration and structural changes in the kidney. Changes in the activity or responsiveness of the renin-angiotensin system (RAS) occur with aging. RAS changes predispose the elderly to various fluid and electrolyte imbalances as well as acute kidney injury and chronic kidney disease. Among the multiple pathways involved in renal aging, the RAS plays a central role. This review summarizes the association of the RAS with structural and functional changes in the aging kidney and age-related renal injury, and describes the underlying mechanisms of RAS-related renal aging. An improved understanding of the renal aging process may lead to better individualized care of the elderly and improved renal survival in age-related diseases.
Acute Kidney Injury/etiology/metabolism/physiopathology ; Age Factors ; Aging/genetics/*metabolism ; Animals ; Glucuronidase/genetics/metabolism ; Humans ; Kidney/*metabolism/physiopathology ; Kidney Diseases/*etiology/genetics/metabolism/physiopathology ; Prognosis ; *Renin-Angiotensin System ; Risk Factors

OBJECTIVETo investigate the effect of tanshinone II(A) on the expression of different components in the renin-angiotensin system of left ventricles of renal hypertensive rats.

METHODThe renal hypertension model was established in rats by the two-kidney-one-clip (2K1C) method. In the experiment, all of the rats were randomly divided into four groups (n = 15 per group) before the operation: the sham-operated (Sham) group, the hypertensive model (Model) group, the low-dose tanshinone II(A) group and the high-dose tanshinone II(A) group. At 5 week after the renal artery narrowing, the third and fourth groups were administered with 35 mg kg(-1) x d(-1) and 70 mg x kg(-1) x d(-1) of tanshinone II(A), respectively. The blood pressure in rats was determined by the standard tail-cuff method in each week after the operation. After the drug treatment for 8 weeks, all the rats were put to death, and their left ventricles were separated to determine the ratio of left ventricle weight to body weight (LVW/BW), the myocardial collagen content, and the expressions of different components in myocardial RAS, including angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), angiotensin 1-type receptor (AT1R), Mas receptor mRNA expression and angiotensin II (Ang II) and angiotensin (1-7) [Ang (1-7)] content.

RESULTCompared with the sham group, the hypertensive model group exhibited a markable increase in the content of Ang II and Ang (1-7) and the mRNA expressions of ACE, ACE2, AT1R and Mas (P < 0.01). However, the treatment with tanshinone II(A) showed the does dependence, inhibited left ventricle hypertrophy, decreased myocardial Ang II content and the mRNA expression of ACE and AT, R in renal hypertensive rats (P < 0. 01) , further increased the myocardial Ang (1-7) content and the mRNA expression of ACE2 and Mas (P < 0.01) , but without any change in the blood pressure of hypertensive rats.

CONCLUSIONThe treatment with tanshinone II(A) could inhibit left ventricle hypertrophy of renal hypertensive rats. Its mechanism may be partially related to the expression of different components in the renin-angiotensin system for regulating myocardial tissues.

Angiotensin I ; genetics ; metabolism ; Angiotensin II ; genetics ; metabolism ; Animals ; Blood Pressure ; drug effects ; Diterpenes, Abietane ; administration & dosage ; Heart Ventricles ; drug effects ; metabolism ; Humans ; Hypertension ; drug therapy ; genetics ; metabolism ; physiopathology ; Male ; Peptide Fragments ; genetics ; metabolism ; Peptidyl-Dipeptidase A ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Renin ; genetics ; metabolism ; Renin-Angiotensin System ; drug effects

The present study was designed to test the hypothesis that a medium-term simulated microgravity can induce region-specific remodeling in large elastic arteries with their innermost smooth muscle (SM) layers being most profoundly affected. The second purpose was to examine whether these changes can be prevented by a simulated intermittent artificial gravity (IAG). The third purpose was to elucidate whether vascular local renin-angiotensin system (L-RAS) plays an important role in the regional vascular remodeling and its prevention by the gravity-based countermeasure. This study consisted of two interconnected series of in-vivo and ex-vivo experiments. In the in-vivo experiments, the tail-suspended, hindlimb unloaded rat model was used to simulate microgravity-induced cardiovascular deconditioning for 28 days (SUS group); and during the simulation period, another group was subjected to daily 1-hour dorso-ventral (-G(x)) gravitation provided by restoring to normal standing posture (S + D group). The activity of vascular L-RAS was evaluated by examining the gene and protein expression of angiotensinogen (Ao) and angiotensin II receptor type 1 (AT1R) in the arterial wall tissue. The results showed that SUS induced an increase in the media thickness of the common carotid artery due to hypertrophy of the four SM layers and a decrease in the total cross-sectional area of the nine SM layers of the abdominal aorta without significant change in its media thickness. And for both arteries, the most prominent changes were in the innermost SM layers. Immunohistochemistry and in situ hybridization revealed that SUS induced an up- and down-regulation of Ao and AT1R expression in the vessel wall of common carotid artery and abdominal aorta, respectively, which was further confirmed by Western blot analysis and real time PCR analysis. Daily 1-hour restoring to normal standing posture over 28 days fully prevented these remodeling and L-RAS changes in the large elastic arteries that might occur due to SUS alone. In the ex-vivo experiments, to elucidate the important role of transmural pressure in vascular regional remodeling and differential regulation of L-RAS activity, we established an organ culture system in which rat common carotid artery, held at in-vivo length, can be perfused and pressurized at varied flow and pressure for 7 days. In arteries perfused at a flow rate of 7.9 mL/min and pressurized at 150 mmHg, but not at 0 or 80 mmHg, for 3 days led to an augmentation of c-fibronectin (c-FN) expression, which was also more markedly expressed in the innermost SM layers, and an increase in Ang II production detected in the perfusion fluid. However, the enhanced c-FN expression and increased Ang II production that might occur due to a sustained high perfusion pressure alone were fully prevented by daily restoration to 0 or 80 mmHg for a short duration. These findings from in-vivo and ex-vivo experiments have provided evidence supporting our hypothesis that redistribution of transmural pressures might be the primary factor that initiates region-specific remodeling of arteries during microgravity and the mechanism of IAG is associated with an intermittent restoration of the transmural pressures to their normal distribution. And they also provide support to the hypothesis that L-RAS plays an important role in vascular adaptation to microgravity and its prevention by the IAG countermeasure.
Angiotensinogen ; genetics ; metabolism ; Animals ; Aorta, Abdominal ; pathology ; physiopathology ; Carotid Artery, Common ; pathology ; physiopathology ; Hindlimb Suspension ; Male ; Muscle, Smooth, Vascular ; metabolism ; pathology ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, Angiotensin, Type 1 ; genetics ; metabolism ; Renin-Angiotensin System ; physiology ; Weightlessness Simulation

OBJECTIVETo evaluate the effect of CYP11B2 gene -344T/C polymorphism on renin-angiotensin-aldosterone system (RAAS) activity and blood pressure in response to hydrochlorothiazide (HCTZ) treatment in Han Chinese patients with essential hypertension.

METHODSEight hundred and twenty-nine patients with mild/moderate essential hypertensive were enrolled. All subjects had their antihypertensive medications withdrawn. After two weeks of wash-out period with placebo, each patient was given 12.5 mg of HCTZ per day for the next six weeks. Physical, biochemical measurements, and the activity of RAAS were taken at the end of the wash-out period (baseline) and 6-week diuretic therapy period. Changes in systolic and diastolic blood pressure were analyzed for association with interaction between genotypes at CYP11B2 -344T/C polymorphism and gender.

RESULTSA total of 776 patients completed the study. 17.5% of subjects have achieved blood pressure normalization after six weeks treatment. For male patients, the aldosterone level with CC genotype was significantly higher than that of those with TT or TC genotype. Following the HCTZ treatment, the blood pressure response in patients with CC genotype was less obvious than that in others, whilst the increase of aldosterone level was greater. For female patients, no association was found between CYP11B2 -344T/C polymorphism and aldosterone level. Following the HCTZ treatment, the blood pressure response in patients with CC genotype was greater than others, whilst the increase of aldosterone activity was less apparent.

CONCLUSIONIn males, the -344T/C polymorphism of CYP11B2 gene is associated with aldosterone level, and the change of aldosterone level was greater, the blood pressure response was weaker after HCTZ treatment. In females, there was no association between this polymorphism and aldosterone level. The change of aldosterone level and blood pressure response to HCTZ were different from that in males.

Antihypertensive Agents ; pharmacology ; Blood Pressure ; drug effects ; genetics ; Cytochrome P-450 CYP11B2 ; genetics ; Female ; Humans ; Hydrochlorothiazide ; pharmacology ; Hypertension ; drug therapy ; enzymology ; genetics ; Male ; Middle Aged ; Polymorphism, Genetic ; Renin-Angiotensin System ; drug effects ; genetics

Genomics ; Renin-Angiotensin System ; drug effects ; genetics

BACKGROUNDGenetic variability in the renin-angiotensin-aldosterone system may modify renal responses to injury and disease progression. The angiotensin I-converting enzyme (ACE) gene insertion/deletion (I/D), the angiotensinogen (AGT) gene, M235T, the aldosterone synthase (CYP11B2) gene, C-344T, and the angiotensin II type 1 receptor (AT1R) gene, A1166C, have been shown to be associated with IgA nephropathy (IgAN) and its progression. We determined the presence of these polymorphisms in 130 Chinese patients with IgAN, including 47 patients with end-stage renal disease (ESRD) and 120 healthy Chinese subjects, to assess their impact on the susceptibility to disease and the liability of progression to ESRD.

METHODSGenotyping was performed with DNA isolated from peripheral leucocytes using polymerase chain reaction amplification of the polymorphic sequence, restriction enzyme digestion, and separation and identification of DNA fragments. Clinical data from renal biopsies were collected.

RESULTSACE, AGT, CYP and AT1R genotype distributions were similar in patients with IgAN and in controls. Comparing patients with ESRD (IgAN-ESRD) and those without ESRD (IgAN-non ESRD), there was a significant increase only in the ACE DD genotype (P < 0.05) among the four gene polymorphisms. There was significant dominance of the male (P < 0.05), more marked hypertension (P < 0.01), proteinuria (P < 0.01) and increased serum creatinine during renal biopsy (P < 0.01) in the IgAN-ESRD group.

CONCLUSIONAmong the ACE, AGT, AT1R and CYP gene polymorphisms, only the DD genotype may predispose the individual to increased risk of progression to ESRD in the Chinese population.

Adult ; Angiotensinogen ; genetics ; Asian Continental Ancestry Group ; genetics ; Cytochrome P-450 CYP11B2 ; genetics ; Female ; Genetic Predisposition to Disease ; Genotype ; Glomerulonephritis, IGA ; genetics ; Humans ; Kidney Failure, Chronic ; genetics ; Male ; Middle Aged ; Peptidyl-Dipeptidase A ; genetics ; Polymorphism, Genetic ; genetics ; Receptor, Angiotensin, Type 1 ; genetics ; Renin-Angiotensin System ; genetics

Glucocorticoid-remediable aldosteronism (GRA) is an autosomal-dominant inheritable form of hyperaldosteronism with early onset hypertension. GRA is caused by unequal crossing-over of the steroid 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. As a result of chimeric gene duplication, aldosterone is ectopically synthesized in the adrenal zona fasciculata under the control of adrenocorticotropin. Here, we describe three cases of GRA in a Korean family. The proband-a 21-yr-old female-was incidentally found to have high blood pressure (170/108 mmHg). Her 46-yr-old father had been treated twice for cerebral hemorrhage at the ages of 29 and 39 yr. Her 15-yr-old brother had a 2-yr history of hypertension; however, he was never treated. Their laboratory test results showed normokalemia, hyporeninemia, hyperaldosteronism, and a high plasma aldosterone concentration-to-plasma renin activity ratio. Normal saline loading failed to suppress aldosterone secretion. However, dexamethasone administration effectively suppressed their plasma aldosterone concentrations. Following genetic analyses with PCR and direct sequencing to document the chimeric gene and crossover site, respectively, we identified CYP11B1/CYP11B2 and determined the breakpoint of unequal crossover to be located between intron 2 of CYP11B1 and exon 3 of CYP11B2.
Adolescent ; Aldosterone/blood ; Aldosterone Synthase/*genetics ; Asian Continental Ancestry Group/*genetics ; Dexamethasone/therapeutic use ; Family ; Female ; Glucocorticoids/*therapeutic use ; Humans ; Hyperaldosteronism/diagnosis/drug therapy/*genetics ; Hypertension/etiology ; Magnetic Resonance Angiography ; Male ; Middle Aged ; Renin/blood/metabolism ; Republic of Korea ; Sequence Analysis, DNA ; Steroid 11-beta-Hydroxylase/*genetics ; Young Adult