angiotensinogen and Ischemia

Recently, the association between AGT M235T polymorphism and ischemic stroke (IS) has attracted widespread attention, and many investigations have been performed. However, the results were inconsistent. Therefore, we performed a meta-analysis to further evaluate the association between M235T and IS. All of the relevant studies were identified from PubMed, EMBASE, Chinese National Knowledge Infrastructure database (CNKI), Chinese Biological Medical Literature database (CBM), Chinese Wanfang and Chongqing VIP database up to January 2013. Statistical analyses were conducted with STATA software version 11.1. Odds ratios with 95% confidence interval were applied to evaluate the strength of the association. We performed the cumulative meta-analysis to assess the tendency of pooled OR over time. Heterogeneity was evaluated by Q-test and the I(2) statistic. The funnel plots and Egger's regression test were used to assess the publication bias. A significant association between AGT M235T polymorphism and IS was found under the dominant model (OR=1.368, 95% CI=1.070-1.749), recessive model (OR=1.66, 95% CI=1.310-2.103), over-dominant model (OR=1.285, 95% CI=1.085-1.523), co-dominant model (OR=1.574, 95% CI=1.276-1.942) and allele model (OR=1.447, 95% CI=1.207-1.735). Besides the Caucasian and the population-based controls, significant association could be found in the subgroup analysis of Asian and hospital-based controls. Results from cumulative analysis showed a tendency of significant association of this polymorphism with IS. However, the opposite trend was observed among Caucasians. Results from our meta-analysis indicated that the AGT M235T polymorphism might be a risk factor for IS among Asians, but not for Caucasians. More studies are required to further confirm our findings.

Topics: Angiotensinogen; Asian People; Databases, Factual; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Ischemia; Methionine; Stroke; Threonine; White People

Topics: Angiotensinogen; Cytokines; Endothelium, Vascular; Epoprostenol; Female; Humans; Hypertension, Pregnancy-Induced; Ischemia; Placenta; Polymorphism, Genetic; Pregnancy; Prognosis; Thromboxane A2

(Pro)renin receptor [(P)RR], a trans-membrane receptor for renin and prorenin, is involved in the local activation of renin-angiotensin system (RAS) in the kidney. However, it remains to be determined whether (P)RR plays a role in the development of ischemic acute kidney injury (AKI).. We examined the abundance of (P)RR, renin/prorenin, angiotensinogen (AGT), AT1 receptor (AT1R), phosphorylation of extracellular signal-regulated protein kinase 1/2 (ERK 1/2) and nuclear factor-κB (NF-κB) by Western blots at 6, 24 and 48 h, and at 7 days after 45-min ischemic injury in rats. Intrarenal angiotensin II (Ang II) levels were determined by radioimmunoassay. We then tested whether the beneficial effects of oral loading of saline solution (1.0 % NaCl) for 7 days prior to ischemic injury were associated with changes in RAS components and ERK 1/2 and NF-κB phosphorylation in the kidney. We also examined the effect of AT1R blocker, olmesartan, on ischemia-induced changes of (P)RR downstream such as AGT and phosphorylation of ERK 1/2.. Renal ischemia increased the abundance of (P)RR protein at 24 h, and peaked at 48 h. (P)RR was mainly stained in the connecting tubules and collecting ducts in control rats, while ischemia increased its immunointensity in the damaged proximal tubules. Renal ischemia increased phosphorylation of ERK 1/2 and NF-κB proteins as early as at 6 h. There was a significant increase in AGT and Ang II levels at 24 and 48 h. Prior saline loading prevented the increase in serum creatinine at 48 h (5.36 ± 1.26 vs. 3.38 ± 1.74 mg/dL, p < 0.05), and suppressed the increases in renal (P)RR, AGT and Ang II contents. Saline drinking also significantly blocked the ischemia-induced increases in phosphorylation of ERK 1/2 and NF-κB. In contrast, although treatment with olmesartan (10 mg/kg/day) for 14 days suppressed an increase of intrarenal AGT, olmesartan did not alleviate ischemic AKI, along with no change of (P)RR and phosphorylated ERK 1/2.. These findings suggest that increased (P)RR is associated with activation of RAS-independent downstream such as ERK 1/2 and NF-κB phosphorylation in the ischemic kidney.

Topics: Acute Kidney Injury; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Creatinine; Extracellular Signal-Regulated MAP Kinases; Imidazoles; Ischemia; Kidney Tubules; Male; NF-kappa B; Phosphorylation; Prorenin Receptor; Proton-Translocating ATPases; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptors, Cell Surface; Sodium Chloride; Tetrazoles; Vacuolar Proton-Translocating ATPases

Sudden cardiac death (SCD) is the leading global cause of mortality, exhibiting increased incidence in patients with diabetes mellitus. Ion channel gene perturbations provide a well-established ventricular arrhythmogenic substrate for SCD. However, most arrhythmia-susceptibility genes, including the KCNE2 K(+) channel β subunit, are expressed in multiple tissues, suggesting potential multiplex SCD substrates.. Using whole-transcript transcriptomics, we uncovered cardiac angiotensinogen upregulation and remodeling of cardiac angiotensinogen interaction networks in P21 Kcne2(-/-) mouse pups and adrenal remodeling consistent with metabolic syndrome in adult Kcne2(-/-) mice. This led to the discovery that Kcne2 disruption causes multiple acknowledged SCD substrates of extracardiac origin: diabetes mellitus, hypercholesterolemia, hyperkalemia, anemia, and elevated angiotensin II. Kcne2 deletion was also a prerequisite for aging-dependent QT prolongation, ventricular fibrillation and SCD immediately after transient ischemia, and fasting-dependent hypoglycemia, myocardial ischemia, and AV block.. Disruption of a single, widely expressed arrhythmia-susceptibility gene can generate a multisystem syndrome comprising manifold electric and systemic substrates and triggers of SCD. This paradigm is expected to apply to other arrhythmia-susceptibility genes, the majority of which encode ubiquitously expressed ion channel subunits or regulatory proteins.

Topics: Anemia; Angiotensin II; Angiotensinogen; Animals; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Diabetes Mellitus; Dyslipidemias; Gene Regulatory Networks; Genotype; Heterozygote; Hyperkalemia; Ischemia; Long QT Syndrome; Mice; Mice, Knockout; Potassium Channels, Voltage-Gated

Neurovascular protection against cerebral ischemia is not consistently observed with a postischemia hypotensive dose of candesartan. The aim of this study was to determine the levels of brain angiotensin II after reperfusion and the efficacy and therapeutic time window of postischemic treatments with hypotensive doses of candesartan for the treatment of cerebral ischemia.. Occlusions of the right middle cerebral artery (60 min) followed by reperfusion were performed using the thread method under halothane anesthesia in Sprague-Dawley (SD) rats. Protein levels of brain angiotensin II and mRNA levels of renin-angiotensin system components were evaluated following reperfusion (n=184 in total). Low-dose or high-dose treatments with candesartan cilexetil (1 or 10 mg/kg per day, respectively) were administered orally immediately following reperfusion once daily for 4 or 7 days (n = 119 in total). An additional group was treated with low-dose candesartan cilexetil after a 12-h delay based on the brain angiotensin II levels (n = 14).. Levels of brain angiotensin II transiently increased 4-12 h after reperfusion, which followed an increase in angiotensinogen mRNA. Candesartan cilexetil treatments significantly reduced blood pressure (BP) in rats administered the high dose and moderately in rats receiving the low dose. A low dose of candesartan cilexetil reduced the infarct size, cerebral edema, and neurological deficits, whereas the high-dose treatments showed limited reductions. Furthermore, oxidative stress following reperfusion was reduced with the low-dose treatments. The therapeutic time window was open for at least 12 h after reperfusion when brain angiotensin II levels had peaked.. Postischemic treatments using low hypotensive doses of candesartan cilexetil provided protection against cerebral ischemic injury and may have a clinically relevant therapeutic time window.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensinogen; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Brain; Brain Edema; Brain Ischemia; Hypotension; Ischemia; Rats; Rats, Sprague-Dawley; Tetrazoles; Time Factors

The remnant kidney model of renal failure is associated with normal or suppressed plasma renin and angiotensin (Ang) II levels when hypertension is established. However, the hypertension responds to angiotensin-converting enzyme (ACE) inhibition and Ang II receptor antagonism, suggesting a role for Ang II in the hypertensive process. Bradykinin (BK) is a potent vasoactive peptide that may also participate in this model.. Ang II and BK peptides were measured in the ischemic peri-infarct portion and the intact portion of the remnant kidney at two, five, and seven weeks after surgery. Plasma Ang II, renin, angiotensinogen, and aldosterone levels were also measured.. Ang II levels in the peri-infarct portion were higher than in the intact portion at all time points and were higher than in sham-operated kidney at two weeks. Ang II levels in the intact portion were similar to the levels in kidneys of sham-operated rats at two and five weeks and were suppressed at seven weeks. BK levels were increased in the peri-infarct portion at all time points and in the intact portion at two and five weeks. Plasma Ang II and aldosterone levels were also elevated at two weeks.. Peri-infarct renal tissue Ang II levels and plasma Ang II and aldosterone levels increase transiently during the evolution of hypertension in the remnant kidney model. Sustained hypertension is associated with an increase in intrarenal BK levels but not with persistent increases in intrarenal or circulating Ang II levels.

Topics: Aldosterone; Angiotensinogen; Angiotensins; Animals; Bradykinin; Infarction; Ischemia; Kidney; Male; Nephrectomy; Peptide Fragments; Rats; Rats, Wistar; Renal Circulation; Renal Insufficiency; Renin

The present studies determined the effect of renal ischemia/reperfusion on components of the intrarenal renin-angiotensin system in rats and evaluated the effect of AT1 angiotensin (ANG) II receptor blockade on functional recovery. After bilateral renal pedicle occlusion for 60 min, serum creatinine increased, peaking at 72 h, and returned to sham levels after 120 h. ANG II levels in ischemic kidneys were significantly increased 24 h after reperfusion but did not differ from levels in sham kidneys after 120 h. Both renal cortical angiotensinogen mRNA and proximal tubular AT1 receptor mRNA were significantly reduced early after reperfusion, returning to sham levels by 120 and 72 h, respectively. AT2 ANG II receptor mRNA was undetectable in proximal tubules from sham rats but was consistently present in ischemic rats at 120 h. By histoautoradiography, we found that binding of 125I-labeled ANG II was preserved in glomeruli but was decreased in whole cortex and outer medulla early after reperfusion and was completely blocked by the AT1 antagonist losartan. Treatment of rats with losartan (25 mg/kg s.c. daily), starting at the time of reperfusion, had no effect on expression of proliferating cell nuclear antigen in cortical tubules but caused a significant decrease in serum creatinine at 72 h (ischemia: 334 +/- 69 microM vs. ischemia + losartan: 135 +/- 28 microM; P < 0.025, n = 6). These data indicate that renal ischemic injury causes an early increase in intrarenal ANG II levels, associated with reduction of mRNA for angiotensinogen and proximal tubular AT1 receptors, and maintenance of glomerular ANG II binding. Losartan accelerates recovery of renal function, suggesting that activation of AT1 receptors impairs glomerular filtration in the postischemic kidney.

Topics: Angiotensin II; Angiotensinogen; Animals; Creatinine; Ischemia; Kidney; Kidney Cortex; Kidney Medulla; Kidney Tubules, Proximal; Losartan; Male; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Reference Values; Reperfusion; RNA, Messenger; Transcription, Genetic; Up-Regulation