Altered Renal Handling of Sodium in Human Hypertension: Short Review of the Evidence (original) (raw)
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Renal mechanisms of genetic hypertension: From the molecular level to the intact organism
Kidney International, 1996
Renal mechanisms of genetic hypertension: From the molecular level to the intact organism. Human primary hypertension is a polygenic disease; its phenotypic expression is modulated by the environment. Though the kidney can play a major role in the initiation and maintainance of hypertension, many questions remain open. Kidney cross-transplantation demonstrated that hypertension can be transplanted with the kidney in all strains of genetically hypertensive rats where such experiments have been carried out. Data consistent with those in rats were also obtained in humans. Many abnormalities in kidney function and ion transport were described in hypertensive rats and humans, but the logical sequence from genetic-molecular to cellular abnormality that causes hypertension via modification of kidney function is difficult to prove. We established this sequence in Milan hypertensive rats using a variety of experimental techniques (isolated kidney and renal cell function, cell membrane ion transport, cross-immunization with membrane proteins, molecular biology, genetic crosses and manipulation). Such studies led to the identification of a polymorphism in the cytoskeletal protein adducin. This polymorphism seems involved in blood pressure regulation both in rats and humans. Preliminary results suggest that adducin polymorphism affects kidney function by modulating the overall capacity of tubular epithelial cells to transport ions modifying the assembly of actin cytoskeleton.
A Possible Primary Role for the Kidney in Essential Hypertension
American Journal of Hypertension, 1989
The role of the kidney in "essential" or "genetic" types of hypertension has been evaluated both in a rat model such as the Milan hypertensive strain (MHS) or in humans. In both species, abnormalities of renal function have been demonstrated before the development of hypertension. Moreover hypertension could be "transplanted" with the kidney when kidney cross-transplantation was carried out between MHS and the Milan normotensive strain (MNS). Also in humans, the familiality for hypertension of the donor affected the requirement of antihypertensive therapy of the recipient. Further studies furnished results that were consistent with the hypothesis that a primary increase in Na transport across the tubular cell could be responsible for the pressor effect of the kidney in MHS or in humans. Because many similarities were found between the function of the tubular cell and the red blood cell in MHS, red blood cells were used to gain information about the molecular genetic mechanisms underlying these cellular changes. The results so far obtained showed that red blood cell abnormalities in MHS were genetically determined within the stem cells and genetically associated with the development of hypertension in F2 hybrids obtained by crossing the Fl (MHS X MNS). Moreover, the abnormal Na transport across the cell membrane may be due to an abnormal function of the membrane skeleton proteins. Studies are in progress to evaluate a possible cause-effect relationship between: membrane skeleton protein-ion transport across the cell membrane and the development of hypertension. Am J Hypertens 1989
The Kidney and Hypertension: Pathogenesis of Salt-Sensitive Hypertension
Current Hypertension Reports, 2012
Salt-sensitive hypertension is closely related with natriuretic capacity of the kidney. Besides several genomewide research reported candidate gene or gene polymorphism responsible for salt-sensitive hypertension, recently, several new factors for acquired salt-sensitive hypertension are reported. Among them, we have identified that Rac1, a small GTPase, activates mineralocorticoid receptor in aldosteroneindependent fashion and induces salt-sensitive hypertension in several rodent model. On the other hand, sympathoactivation in the brain and/or kidney regulate sodium handlings in the kidney. Recently it is reported that oxidative stress in the brain or in the kidney may modulate sympathetic tone. Moreover, we reported that β2 adrenoceptor alters histone acetylation and further regulates sodium resorption at distal tubules via activating glucocorticoid receptor. These regulations are to be confirmed in humans and the future, this epigenetic marker may open a new door for diagnosis and treatment of saltsensitive hypertension or moreover preventing development of salt-sensitive hypertension.
Kidney & blood pressure research, 2018
One potential pathomechanism how low nephron number leads to hypertension in later life is altered salt handling. We therefore evaluated changes in electrolyte and water content in wildtype (wt) and GDNF+/- mice with a 30% reduction of nephron number. 32 GDNF+/- and 36 wt mice were fed with low salt (LSD, 0.03%, normal drinking water) or high salt (HSD, 4%, 0.9% drinking water) diet for 4 weeks. Blood pressure was continuously measured by telemetry in a subgroup. At the end of the experiment and after standardized ashing processes electrolyte- and water contents of the skin and the total body were determined. We found higher blood pressure in high salt treated GDNF+/-compared to wt mice. Of interest, we could not confirm an increase in total-body sodium as predicted by prevailing explanations, but found increased total body and skin chloride that interestingly correlated with relative kidney weight. We hereby firstly report significant total body and skin chloride retention in salt ...
High-salt diet reveals the hypertensive and renal effects of reduced nephron endowment
AJP: Renal Physiology, 2010
The extent to which a reduced nephron endowment contributes to hypertension and renal disease is confounded in models created by intrauterine insults that also demonstrate other phenotypes. Furthermore, recent data suggest that a reduced nephron endowment provides the “first hit” and simply increases the susceptibility to injurious stimuli. Thus we examined nephron number, glomerular volume, conscious mean arterial pressure (MAP), and renal function in a genetic model of reduced nephron endowment before and after a high-salt (5%) diet. One-yr-old glial cell line-derived neurotrophic factor wild-type (WT) mice, heterozygous (HET) mice born with two kidneys (HET2K), and HET mice born with one kidney (HET1K) were used. Nephron number was 25% lower in HET2K and 65% lower in HET1K than WT mice. Glomeruli hypertrophied in both HET groups by 33%, resulting in total glomerular volumes that were similar between HET2K and WT mice but remained 50% lower in HET1K mice. On a normal-salt diet, 24...
Renal dysfunction as a possible cause of essential hypertension in predisposed subjects
Kidney International, 1983
Renal dysfunction as a possible cause of essential hypertension in predisposed subjects. In 65 young normotensive subjects with two hypertensive parents (HP), and in 55 matched subjects with two normotensive parents (NP), the following factors were measured: renal plasma flow (RPF), glomerular filtration rate (GFR) both as mutest® and creatinine clearances; 24-hr urinary output; plasma renin activity (PRA); Na and K in plasma and in 24-hr urine and 24-hr urinary excretion of aldosterone. In 30 HP and in 34 NP, the cardiac output and plasma concentrations of noradrenaline, adrenaline, and dopamine were also measured in the supine position and after 10 mm of standing. The HP have greater RPF (P < 0.01), faster GFR (P < 0.02), greater 24hr urinary output (P < 0.05), and lower PRA (P < 0.01) than the NP. All the other factors were similar in the two groups of patients. It is proposed that the differences in renal function in the HP and the NP may be due to an abnormality in tubular handling of ions and water in the HP, which may be responsible for the increase in blood pressure in a proportion of patients with essential hypertension.