Renin and Human Kidney Research

Markers of cardiovascular disease risk after hypertension in pregnancy

2011-12-22T10:41:00.000-06:00

Mangos GJ, Spaan JJ, Pirabhahar S, Brown MA.
SourceDepartments of Medicine and Renal Medicine, St George Hospital, University of New South Wales, Kogarah, New South Wales, Australia.

Abstract
OBJECTIVES: Women with a history of preeclampsia or gestational hypertension have an increased risk of cardiovascular disease. Underlying cardiovascular risk factors, persistent endothelial dysfunction or sympathetic overactivity may contribute to this risk. We studied markers of cardiovascular disease risk in nonpregnant women with a history of hypertension in pregnancy.

METHODS: Women with a history of preeclampsia (n = 39), gestational hypertension (n = 27) and normal pregnancies (n = 35) were studied 2-12 years after delivery. Laboratory measures included plasma fasting lipids, glucose, insulin, creatinine and urinary albumin-to-creatinine ratio. Blood pressure was measured by 24-h ambulatory blood pressure monitoring, endothelial function by flow-mediated dilatation and sympathetic activity by both head-up tilt test and cold pressor test, including the response of the circulating renin-angiotensin system to tilt testing.

RESULTS: Compared with women who had previous normal pregnancies, women with a history of preeclampsia or gestational hypertension have higher ambulatory blood pressure, BMI and relative insulin resistance. Glomerular filtration rate, albumin-to-creatinine ratio, endothelial function and sympathetic activity was similar among the three groups.

CONCLUSION: Women with a history of preeclampsia or gestational hypertension have features of the metabolic syndrome which are presumably present already before pregnancy, predisposing them to hypertensive disorders of pregnancy and later cardiovascular risk. In this study, we found no evidence for early renal damage, endothelial dysfunction or sympathetic overactivity in the postpartum state.

RENIN Blood test could predict best hypertension drugs

2010-09-16T16:42:00.001-05:00

Drugs prescribed to lower blood pressure may actually raise it in some patients, according to new research. A related study suggests patients be given a blood test to avoid this problem and ensure they get the hypertension drug that’s best for them.

In one study, researchers at the Albert Einstein College of Medicine in the Bronx, N.Y., looked at blood levels of renin, an enzyme that regulates blood pressure, in 945 people who took part in a workplace hypertension study in New York City between 1981 and 1998. Researchers found that in some cases, people with low renin levels who were prescribed a calcium channel blocker or an ACE inhibitor — both of which inhibit renin function — were more likely to see an increase in their systolic blood pressure.

In the second study, scientists at the Mayo Clinic in Rochester, Minn., studied 363 men and women age 65 and younger with hypertension. Participants’ renin levels were measured, and those with high levels were more likely to respond to atenolol, a common beta blocker, than to the diuretic hydrochlorothiazide. The results were the same regardless of race, age, and other patient characteristics.

The findings suggest that current hypertension treatment guidelines may need some revision, said Dr. Curt Furberg of Wake Forest University School of Medicine, author of an accompanying editorial on the studies. “Prescription of the ‘wrong’ drug . . . could trigger a pressor response that could undermine the whole premise of antihypertensive treatment,’’ he said.

BOTTOM LINE: Measuring levels of the enzyme renin could help physicians prescribe more effective hypertension drugs.

CAUTIONS: Patients most likely to benefit from tests to measure renin levels are those who are taking anti-hypertensive drugs for the first time or who are taking two or more drugs.

WHERE TO FIND IT: American Journal of Hypertension, online Aug. 18

The Role of Renin–Angiotensin System Blockade

2010-01-28T14:40:00.000-06:00

The renin–angiotensin system (RAS) plays key roles throughout the cardiovascular continuum, and blockade of this system—either through angiotensin-converting enzyme (ACE) inhibition or through angiotensin II type 1 (AT1) receptor antagonism—now occupies a central place in the management of cardiovascular disease (CVD).

Understanding of the RAS has expanded in recent years with the identification of new pathways for formation of angiotensin II and novel effector peptides, such as angiotensin-(1–7), which may constitute new therapeutic targets. A substantial proportion of the benefits of ACE inhibitors, including vasodilation, improvements in endothelial function, and inhibition of cell proliferation, appear to be attributable to decreases in angiotensin II and increases in bradykinin.

In addition, however, there is evidence that other mechanisms, such as modulation of ACE signaling, may also contribute. Angiotensin receptor blockers (ARBs) selectively block AT1 receptors and allow unopposed stimulation of AT2 receptors, with potentially beneficial vasodilatory, anti-inflammatory, and antiproliferative effects.

As a result, these agents share many of the clinical benefits of ACE inhibitors. Both ACE inhibitors and ARBs have been shown to exert multiple antiatherogenic actions, and to reduce clinical events in high-risk participants; their use is recommended in current guidelines for the secondary prevention of CVD

The American Journal of Cardiology, Volume 105, Issue 1, Pages 10A-20A
J. Probstfield, K. O'Brien

Renin and Prorenin Activate Pathways Implicated in Organ Damage in Human Mesangial Cells Independent of Angiotensin II Production

2009-11-24T14:33:00.000-06:00

American Journal of Nephrology Vol. 30, No. 3, 2009

Background: The mechanism by which an activated renin-angiotensin system (RAS) leads to the development of renal diseases, such as fibrosis, is only partially explained by the downstream effects of angiotensin II. The discovery of a receptor that binds renin and prorenin, and the consequent production of profibrotic molecules, revealed a novel axis within the RAS pathway that may contribute to the pathogenesis of organ damage in patients with elevated renin and/or prorenin levels.

Methods: To better understand the genes and networks underlying the receptor-mediated effects of renin and prorenin, a gene expression profiling study was performed on human mesangial cells in the presence of angiotensin-II-blocking agents.

Results: Renin and prorenin induce highly overlapping gene expression signatures that are dependent, only in part, on the presence of the (pro)renin receptor. We found that 2 distinct pathways were activated by renin and prorenin: a TGF-dependent pathway and a TGF-independent pathway. Bioinformatic analysis was used to show that both pathways are highly enriched with genes implicated in fibrosis, hypertrophy and atherosclerosis.

Conclusions: This study suggests that both renin and inactive prorenin are capable of inducing genetic programs that could contribute to end-organ damage and atherogenesis, through receptor-mediated angiotensin-independent mechanisms.

Cardiovascular and Renal Surrogate Markers in the Clinical Management of Hypertension

2009-07-07T14:49:00.000-05:00

INTRODUCTION: Surrogate markers represent a significant contribution to early diagnosis, longitudinal prognoses, and outcome prediction in cases of hypertension. They often enable detection of disease and disease potential when the disease is still subclinical and are useful noninvasive tools for designing and evaluating therapeutic programs. Surrogate markers are increasingly employed as predictive endpoints for treatment.

METHODS: Key studies supporting the importance of surrogate markers as diagnostic and prognostic predictors of cardiovascular and renal clinical outcomes in hypertension, as well as what is known about the effects of renin-angiotensin-aldosterone system-blocking agents on these biomarkers were reviewed. RESULTS: Clinical data supporting the use of surrogate markers for heart failure, such as brain natriuretic peptide (BNP) and N-terminal prohormone BNP; markers for renal function, such as urinary albumin to creatinine ratio (UACR), urinary albumin excretion rates (UAER), and creatinine, reflecting glomerular filtration; and markers of cardiac remodeling, such as left ventricular hypertrophy and calculations of left ventricular mass index (LVMI), were reviewed for their utility in improving prognosis and treatment efficacy. Finally, hypertension treatment with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and potentially direct renin inhibitors can significantly improve outcomes predicted by surrogate markers.

CONCLUSIONS: BNP, UACR, UAER, and LVMI, among others, have been increasingly established as valid surrogate markers with significant value for hypertension prognosis and therapy. The benefits of using surrogate markers to gauge the effectiveness of hypertension therapy in reducing renal and cardiac complications can be seen in improved morbidity and mortality

Coronary Care Unit and Heart Failure Program, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, Cardiology Section, mc 9111A, San Diego, CA, 92161, USA,

Emerging therapies for chronic kidney disease: what is their role?

2009-05-22T12:45:00.000-05:00

The prevalence of chronic kidney disease (CKD) is increasing worldwide. The best therapies currently available focus on the control of blood pressure and optimization of renin-angiotensin-aldosterone system blockade. Currently available agents are only partially effective against hard end points such as the development of end-stage renal disease and are not discussed in this Review. Many other agents have been shown to reduce proteinuria and delay progression in animal models of CKD. Some of these agents, including tranilast, sulodexide, thiazolidinediones, pentoxifylline, and inhibitors of advanced glycation end-products and protein kinase C, have been tested to a limited extent in humans. A small number of randomized controlled human trials of these agents have used surrogate markers such as proteinuria as end points rather than hard end points such as end-stage renal disease or doubling of serum creatinine level. Emerging therapies that specifically target and reverse pathological hallmarks of CKD such as inflammation, fibrosis and atrophy are needed to reduce the burden of this chronic disease and its associated morbidity. This Review examines the evidence for emerging pharmacological strategies for slowing the progression of CKD.

Westmead Hospital, Westmead, NSW, Australia.

Renin

2007-11-14T12:28:00.001-06:00

Renin also known as angiotensinogenase, is a circulating enzyme that activates the renin-angiotensin systemby producing angiotensin I from angiotensinogen. Human Reninis released mainly by juxtaglomerular cells in the juxtaglomerular apparatus of the kidneys in response to low blood volume or decreased serum NaCl concentration, mediated through the rapid release of prostaglandins. Although it has hormone-like actions, it cleaves a protein precursor in the circulation rather than working on a cellular target. Thus it is not truly a hormone [1]. Sympathetic activation of membrane β1- and α1-adrenergic receptors on JGA cells also cause renin release, probably by altering tubular sodium content or macula densa function. [2] The normal concentration in adult human plasma is 1.98-24.6 ng/L in the upright position. [3]

The primary structure of renin precursor consists of 406 amino acids with a pre and a pro segment carrying 20 and 46 amino acids respectively. Mature Renin contains 340 amino acids and has a mass of 37 kD.

Renin activates the renin-angiotensin system by cleaving angiotensinogen, produced by the liver, to yield angiotensin I, which is further converted into angiotensin II by ACE , the angiotensin-converting enzyme primarily within the capillaries of the lungs. Angiotensin II then constricts blood vessels, increases the secretion of ADH and aldosterone, and stimulates the hypothalamus to activate the thirst reflex, leading to increased blood pressure.

1.J. Clin. Invest. 114:805-812 (2004).
2.Brenner & Rector's The Kidney, 7th ed., Saunders, 2004. pp.2118-2119
3.Hamilton Regional Laboratory Medicine Program - Laboratory Reference Centre Manual.