Mini-ReviewEffects of renin–angiotensin system blockade in the aging kidney
Introduction
The natural process of aging is associated with a progressive modification and ultimately a loss of organ function. These changes are common to all species. In general, a correlation exists between the structural and functional alterations associated with aging. In mammals, degenerative processes such as arteriosclerosis, the development of senile plaques in the brain and the replacement of functional parenchyma by fibroconnective tissue in a variety of organs, are considered manifestations of aging. The kidney also participates in the aging process, and much attention has been devoted to studying the effects of aging on the kidney.
The essential role of the kidneys is to eliminate waste products and fluids excess. The kidneys are also involved in the regulation of the body electrolytical balance. It is a well-known fact that the kidney function becomes slightly lower with aging. These progressive changes include the renal vasculature, and the urinary system. A short summary of the structural and functional changes associated with aging are described in Table 1.
The kidneys progressively reduce their size during aging. This decrease is accompanied by lower renal blood flow and glomerular filtration rate (GFR). The kidney function has an additional capacity, which is not evident under normal conditions, ‘the renal reserve’. Kidney function remains apparently normal in aged humans and animals but, in fact, it has lost the reserve function. Renal histological lesions that appear during aging confirm this situation.
Kidney lesions related to the aging process are widely observed in different animals species. Kidney damage as well as its consequence, the declination of GFR, are considered physiologic processes. We use the Cockcroft–Gault formula, taking also the age into account, to determine the creatinine clearance. The creatinine clearance (in ml/min) in men is calculated: (140−age)×body weight (kg)/72×serum creatinine (mg/dl); in women, by multiplying the result by 0.85 (Cockcroft and Gault, 1976).
During the last 20 years, we have investigated the mechanisms and alterations due to aging involved in this process. Our studies were mainly related to the kidney and the cardiovascular system, but the brain, liver, penis, and gut have been also analyzed. We have been particularly interested, in the role played by the renin–angiotensin system (RAS) in the aging process through its effect on oxidative stress, considered a trigger of inflammatory and profibrotic pathways involved in the tisular changes of the senescent organs.
In a former report (Ferder et al., 1993), we found that mice chronically treated with enalapril, showed a reduction of age-associated renal and cardiovascular damage and an increase in the number of mitochondria in kidney, myocardium and liver tissues. This protective action was associated with an increase in the survival of treated mice. We also showed that enalapril and captopril can alter the oxidant/antioxidant balance in favor of the latter, probably protecting cells from oxidative damage (Cavanagh et al., 1997, Cavanagh et al., 2000). Likewise, in a model of aged mice, the inhibition of the RAS suggests the existence of a connection among improvement of antioxidant enzyme activity, mitochondrial number, myocardiocyte replicative capacity, apoptosis and myocardial fibrosis (Ferder et al., 1998).
Section snippets
Effects of aging on the kidney
The progressive development of glomerulosclerosis is a well-known alteration that occurs in the aging kidney. In both humans and rats, the development of glomerulosclerosis is a biologic characteristic of aging.
The number of functional glomeruli declines roughly in accord with renal weight decrease. We found, in aged mice, 25% of remaining glomeruli in the renal cortex, compared with younger animals (Ferder et al., 1994). The incidence of sclerotic glomeruli rises with advancing age, increasing
Heart and vessels
In rats, aging produces an increase in left ventricular weight and myocardial fibrosis (Michel et al., 1988). On the other hand, enhanced stiffness is the main alteration of arterial wall structure during aging. This change is mostly related to smooth muscle cell hypertrophy and collagen accumulation. Endothelial and smooth muscle dysfunction with aging has also been described in the rat aorta.
AngII has structural effects on the cardiovascular system. Actually, it can modify vascular structure
Mechanisms by which ACE inhibitors and angiotensin II antagonists may alter the aging process
Under physiological conditions, mitochondrial respiration is considered the most important source of ROS, mitochondrial-DNA, proteins and lipids are the main target of these oxidant compounds (Cadenas and Davies, 2000).
The possibility that alterations in the mitochondrial genome are decisive in the aging process is compatible with those studies demonstrating that mitochondrial DNA is more prone to mutation than nuclear DNA (Hart and Turturro, 1983). The fact that mitochondrial changes are
Conclusions
Our working hypothesis is that AngII inhibition produces changes in the mechanism of oxidative stress specially at the mitochondrial level. These effects may protect from deletion of mitochondrial DNA. Prevention of both mitochondrial damage and decreased mitochondrial number might be involved in the delay of the normal aging process in different tissues including kidneys. The lower rate of oxidative stress could be a key to reduction in inflammatory process and cytokine and growth factor
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