Angiotensin II receptor subtypes in the kidney: Distribution and function (original) (raw)

Angiotensin I1 (AII) is a powerful humoral regulator of body fluid and electrolyte balance and arterial blood pressure. In the kidney, A11 influences renal haemodynamics and proximal tubular reabsorption of sodium through activation of A11 receptor that mediate complex signal transduction pathways. Angiotensin I1 is also implicated in the pathophysiological process of some progressive renal diseases. Pharmacological characterization and molecular cloning of A11 receptor reveals at least two major subtypes of A11 receptors, AT, and AT2, in the kidney and other tissues. The AT, receptor cDNA encodes a 359 amino acid protein with structure typical of seven transmembrane G-protein coupled receptors. Two isoforms of AT, receptor, AT,, and ATlB, are known in rodents, but probably only one occurs in other mammals including humans. The AT2 receptor cDNA, a 363 amino acid protein, shares only 32% identical amino acid residues with AT, receptor, although it also has a seven transmembrane domain topology. In adult mammalian kidneys, AT, receptors predominate in the glomerular mesangium, proximal tubular epithelium, renomedullary interstitial cells in the inner stripe of the outer medulla and large preglomerular vessels except those in human and monkey where AT2 receptors predominate. By contrast, in foetal kidneys, AT2 receptors are the major subtype; however, this shows dramatic regulation during development. Physiological studies using ATl selective antagonists show that the known actions of A11 on renal haemodynamics, glomerular filtration, and tubular sodium and water transport are mediated by this subtype of A11 receptors. In addition, AT1 receptors also mediate hypertrophic and mitogenic actions of A11 on cultured glomerular mesangial cells and proximal tubular epithelial cells, and on extracellular matrix accumulation in animal models of progressive renal diseases. By contrast, blockade of AT2 receptors has no effect on renal haemodynamics, tubular sodium reabsorption or growth properties of AIL Overall, A11 exerts multiple actions in the kidney by interacting with different subtypes of AII receptors located on multiple cellular sites. ure, to adjust glomerular filtration rate and tubular reabsorption of fluid and electrolytes in order to maintain fluid and electrolyte balance and arterial blood pressure homeostasis. l-4 Among several humoral influences, angiotensin I1 (AII) is one of most powerful mechanisms involved in these p r o c e s s e~.~~~-~ Angiotensin 11, formed either systemically or locally, has diverse effects on the kidney, including the control of intrarenal haemodynami~s,~~7~~ stimulation of proximal tubular reabsorption of sodium, fluid and bicarbon-ate21596 and modulation of urine concentrating and diluting proces~es.'~~ These renal actions of AII are mediated by specific receptors localized on glomerular