摘要:

Transgenic and gene-targeting techniques have opened a new era of physiologic investigation: the field of functional genomics. The nearly exclusive use of the mouse in this discipline has necessitated the development and adaptation of sophisticated techniques for evaluating murine physiology at the cellular, tissue, organ and whole animal levels. Although many of the methodologies for exploring cardiorenal function have been successfully adapted from their use in the rat, there are important limitations and considerations that must be recognized when applying them in the mouse. Investigators have been successful in measuring a wide variety of functional variables at the whole kidney and even single nephron levels. Reviewed here are recent advances in the measurement of blood pressure, renal blood flow, whole kidney electrolyte excretion and clearance rates, single-nephron glomerular filtration rate and transport, and tubuloglomerular feedback.

ISSN:1062-4821    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Efforts to identify hypertension-predisposition genetic loci have focused largely on candidate gene strategies, in which specific candidates have been tested for linkage and association with blood pressure or the diagnosis of hypertension. A variety of candidate genes have been investigated, including loci involving the renin-angiotensin-aldosterone system, sodium epithelial channel, catecholaminergic/adrenergic function, renal kallikrein system, α-adducin, and others involving lipoprotein metabolism, hormone receptors, and growth factors. These studies, and more recently, several genome-wide scans, have yielded highly promising results suggesting a number of potential candidate genes and genomic regions that may contribute to blood pressure variation. The results also point to the need for more robust phenotypes that are intermediate in the pathogenetic development of high blood pressure. Additional methods and strategies for improving genetic studies of human hypertension include comparative genomics, in which results from animal studies are used to target potential blood pressure loci, the use of newly developed quantitative tests of linkage and association, comprehensive single-nucleotide polymorphism discovery in candidate loci, and the use of single-nucleotide polymorphisms in cladistic/haplotype analyses and genome-wide searches.

ISSN:1062-4821    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Recent studies indicate that arachidonic acid is primarily metabolized by cytochrome P450 enzymes of the 4A and 2C families in the kidney to 20-hydroxyeicosatetraenoic acid (HETE), epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids. These compounds play central roles in the regulation of renal tubular and vascular function. 20-HETE is produced by renal vascular smooth muscle (VSM) cells and is a potent constrictor that depolarizes VSM cells by blocking the calcium-activated potassium channel. Inhibition of the formation of 20-HETE blocks the myogenic response of isolated renal arteriolesin vitro, and autoregulation of renal blood flow and tubuloglomerular feedback responsesin vivo. EETs are products formed in the endothelium and are potent dilators that activate the calcium-activated potassium channel in renal VSM. Endothelial-dependent vasodilators stimulate the release of EETs, and these compounds appear to serve as an endothelial-derived hyperpolarizing factor. EETs and 20-HETE are produced in the proximal tubule. There, they regulate sodium/potassium-ATPase activity and serve as second messengers for the natriuretic effects of dopamine, parathyroid hormone and angiotensin II. 20-HETE is also produced in the thick ascending loop of Henle. It regulates sodium-potassium-chloride transport in this nephron segment. The renal production of cytochrome P450 metabolites of arachidonic acid is altered in hypertension, diabetes, toxemia of pregnancy, and hepatorenal syndrome. Given the importance of cytochrome P450 metabolites of arachidonic acid in the control of renal function, it is likely that changes in this system contribute to the abnormalities in renal function that are associated with many of these conditions.

ISSN:1062-4821    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Cyclooxygenase metabolizes arachidonic acid to a family of bio-active fatty acids designated prostaglandins. Two isoforms of cyclooxygenase exist, designated COX1 and COX2. These isoforms are expressed in distinct but important areas of the kidney. COX1 predominates in vascular smooth muscle and collecting ducts, whereas COX2 predominates in the macula densa and nearby cells in the cortical thick ascending limb. COX2 is also highly expressed in medullary interstitial cells. Whereas COX1 expression does not exhibit dynamic regulation, COX2 expression is subject to regulation by several environmental conditions, including salt intake, water intake, medullary tonicity, growth factors, cytokines, and adrenal steroids. Recently, COX2-selective non-steroidal anti-inflammatory drugs have become widely available. Many of the renal effects of non-selective non-steroidal anti-inflammatory drugs (including sodium retention, decreased glomerular filtration rate, and effects on renin-angiotensin levels) appear to be mediated by the inhibition of COX2 rather than COX1. Therefore, in contrast to the gastrointestinal-sparing effects of COX2-selective non-steroidal anti-inflammatory drugs, when considering the kidney, the same caution must be applied when using COX2-selective inhibitors as has been used with traditional non-selective non-steroidal anti-inflammatory drugs.

ISSN:1062-4821    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

The angiotensin type 2 receptor is one of two major angiotensin II receptors that has been identified, cloned and sequenced. The other major receptor, the angiotensin type 1 receptor, is thought to mediate most of the biological responses to the peptide. The angiotensin type 2 receptor is expressed heavily in fetal tissues, but only at a low level in the adult. Documented angiotensin type 2 receptor expression sites in the adult include kidney, heart and mesenteric blood vessels. The function of the angiotensin type 2 receptor is just beginning to be explored. Most of the evidence suggests that the angiotensin type 2 receptor mediates a vasodilator signalling cascade that includes bradykinin, nitric oxide and cyclic guanosine 5-monophosphate. At least some of the beneficial actions of angiotensin type 1 receptor blockade, such as hypotension, are mediated by stimulation of the angiotensin type 2 receptor. Several recent papers suggest that angiotensin type 2 receptors, presumably located in systemic blood vessels, mediate vasodilation and hypotension. The angiotensin type 2 receptor may be a new therapeutic target and candidate gene for the pathophysiology of hypertension.

ISSN:1062-4821    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Blockade of the renin-angiotensin-aldosterone system has proved effective in retarding the progression of renal disease in the remnant kidney model, as well as other experimental diseases, and most importantly, in a range of progressive human renal diseases. Attention has focused on the role of angiotensin II in propagating progression both by its hemodynamic and non-hemodynamic actions. Recent evidence, predominantly in the remnant kidney model, indicates that the drugs used to block this hormone system, angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, also lower aldosterone levels. Aldosterone as well as angiotensin II thus appears to be instrumental in sustaining the hypertension and fibroproliferative destruction of the residual kidney.

ISSN:1062-4821    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

Many studies have attempted to relate genetic variants of components of the renin-angiotensin system to complex diseases such as essential hypertension, cardiovascular disease and progressive renal failure. The angiotensin II type 1 receptor (AT1R) gene is an important example of this approach. Many polymorphisms of the AT1R gene have been identified, but the A1166→C polymorphism has been the most extensively studied. The physiological significance of this polymorphism is uncertain because of its location in the 3′-untranslated region of the gene. The present review summarizes association studies of the AT1R gene, focusing on clinical end-points and physiological responses.

ISSN:1062-4821    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:1062-4821    

出版商:OVID    

年代:2001

数据来源: OVID