Renin Angiotensin Aldosterone System (RAAS): its biology and drug targets for treating diabetic nephropathy (original) (raw)
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Pakistan journal of pharmaceutical sciences
Diabetes mellitus is a multifactorial disorder of hyperglycemia caused by a combination of biochemical, molecular and genetic factors, which leads to the dysfunction of various organs including kidneys. Diabetic nephropathy (DN) is one of the microvascular complications of diabetes that results due to poor glycemic control. Several molecular and biochemical pathways have been implicated in the pathogenesis of DN. Of these, the Renin Angiotensin Aldosterone System (RAAS) is considered as a key pathway. RAAS involves various subsystems which contribute to the development of DN. Mutations in several genes of the RAAS pathway have been associated with the development of DN. These genes or their products present them as therapeutic targets for potent drugs to control or prevent DN, and development of new drugs for targeting the RAAS. Drugs in use for DN are mainly the Angiotensin Converting Enzyme (ACE) inhibitors, Angiotensin Receptors Blockers (ARB) and renin inhibitors which play impo...
F1000 Medicine Reports, 2010
Diabetic nephropathy (diabetic kidney disease) is defined as a rise in urinary albumin excretion rate, often associated with an increase in blood pressure, and typically with concomitant retinopathy but without evidence of other causes of renal disease. It is characterized first by albuminuria and then by a progressive decline in glomerular filtration rate, eventually resulting in end-stage renal disease (ESRD). Diabetic nephropathy occurs in approximately 30-35% of type 1 and type 2 patients and tends to cluster in families. Diabetic kidney disease is associated with a very marked increase in cardiovascular disease and, even from the earliest stages, with microalbuminuria. A diabetic milieu is required for the diabetic glomerular lesion to develop, and the renin angiotensin aldosterone system (RAAS) has been implicated in the development and progression of diabetic nephropathy. Most patients with diabetes and renal impairment die from a cardiovascular disease event before they progress to ESRD. From the studies described in this review, we think that clear evidence of RAAS inhibition in the prevention of diabetic nephropathy is lacking and more studies are warranted. Nevertheless, tight blood pressure control with inhibitor of RAAS and multifactorial intervention (glycaemic, lipid control and so on) are warranted for secondary prevention and treatment of chronic kidney disease in diabetes.
highlight that both DM and hypertension exacerbate each other in terms of subsequent complications (Cooper & Johnston, 2000) increasing the burden of social dysfunction and high risk of premature death. DM is a chronic metabolic disorder characterized by hyperglycemia and insufficiency of secretion or action of endogenous insulin. Nowadays, diabetes afflicts around 6.6% of the global adult population, or approximately 285 million individuals, and this is projected to increase by more than 50% to a 7.8% worldwide prevalence in 20 years. Considering that DM is an important health problem and it has been recognized as a major risk factor for the development of complications in target organs, including retinopathy, neuropathy, nephropathy and cardiovascular disease, the comprehension of the mechanisms involved in the association among diabetes is the subject of many research groups (International Diabetes Federation, 2009).
Role of the renin angiotensin system in diabetic nephropathy
World Journal of Diabetes, 2010
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Renin-Angiotensin-Aldosterone system inhibition in prevention of diabetes mellitus
Romanian journal of internal medicine = Revue roumaine de médecine interne, 2004
The number of people with diabetes grows worldwide. The complications resulting from this disease are a significant cause of morbidity and mortality. World Health Organization estimates that, while in the year 2000 the number of people with diabetes was about 177 million, by 2025, this will increase to at least 300 million. The diabetes epidemic, without primary prevention, will continue to grow. Individuals with type 2 diabetes are at a significantly higher risk for coronary heart disease, peripheral vascular disease, and stroke, and they have a greater probability of having hypertension, dyslipidemia, and obesity. A number of clinical trials provide evidences that RAAS inhibition could be helpful at preventing new onset of type 2 diabetes mellitus. Pharmacologic treatment that antagonize the renin-angiotensin system (RAS) provide more benefits, not only in patients after myocardial infarction and in congestive heart failure, but also in persons with hypertension and type 2 diabete...
Inhibition of the renin–angiotensin system and chronic kidney disease
International Urology and Nephrology, 2008
Chronic kidney disease (CKD), a major worldwide public-health problem which affects about 10% of the population, has an increased annual incidence rate of about 5-8%. This increased incidence is mainly due to type 2 diabetes and hypertension and the increasing incidence of elderly patients with CKD. Although the progression to end-stage renal failure (ESRF) is mainly based upon the underlying disease, comorbid conditions such as an initial low renal function, severe proteinuria, and high levels of blood pressure also play important roles in the development of ESRF. Since experimental and clinical evidence suggest that angiotensin II plays a central role in the progression of CKD, pharmacological inhibition of the renin-angiotensin-aldosteron system (RAAS) with angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists has been suggested as firstline treatment for hypertension and prevention of ESRF in these patients. Aliskiren, a novel renin inhibitor is also a promising medical intervention. However, independently of the category of the drugs used, low target blood pressure levels seem to be equally or more important for the delay or prevention of CKD. In this review the results of studies with pharmacological inhibition of the RAAS in patients with diabetic and nondiabetic nephropathy is discussed.
Blockade of the renin–angiotensin system for the primary prevention of diabetic nephropathy
Diabetes management, 2012
The prevention of chronic kidney disease is a primary goal for diabetes management. Lowering blood pressure can reduce the incidence of microalbuminuria in Type 1 or Type 2 diabetes, especially in patients with hypertension. Blockade of the renin-angiotensin system (RAS) is an effective strategy to reduce blood pressure in diabetic patients, but no more so than other antihypertensive strategies. RAS blockers have a more favorable side-effects profile compared to other antihypertensive agents, meaning that generally patients are more likely to take them. Any 'independent' effect of RAS blockade for the primary prevention of diabetic nephropathy, beyond blood-pressure control, remains to be clearly established. New combination strategies using renin inhibitors or aldosterone antagonists, to achieve a more complete RAS blockade, have the potential to improve renal outcomes in patients with diabetes. Summary There is clear evidence for the pathogenic role of the renin-angiotensin system (RAS) in the progression of diabetic kidney. Treatment with either an a ngiotensin-converting enzyme inhibitor or angiotensin receptor blocker have been shown to reduce proteinuria and preserve renal function in patients with diabetes and chronic kidney disease. While such data provide a strong rationale for early and sustained blockade of the RAS for the primary prevention of kidney disease, clinical trial evidence to support this goal is limited and inconsistent. By contrast, data from observational and clinical trials clearly demonstrate the primacy of blood-pressure control in the development of diabetic kidney disease, especially in hypertensive patients. Whether RAS blockade offers additional benefits for primary prevention, over-and-above blood-pressure control, remains contentious. At best, any 'independent effects' on primary prevention are modest, and certainly not the panacea envisaged by many practitioners. However, the better tolerability, efficacy and side-effects profile of RAS blockers, and other actions on retinopathy and cardiovascular disease, means that most patients with diabetes currently receive RAS blockers as first line antihypertensive agents. The future development of more effective 'escape-proof' regimens currently offers the best way forward to realize the hope that RAS blockade will ultimately prevent diabetic kidney disease in the clinic as effectively as it does in animal models.