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An association between low nephron number and subsequent development of hypertension in later life has been demonstrated. The underlying pathomechanisms are unknown, but glomerular and postglomerular changes have been discussed. We investigated whether such changes are already present in prehypertensive "glial cell line-derived neurotrophic growth factor" heterozygous mice (GDNF+/-) with lower nephron number. Twenty-six-week-old mice [22 GDNF+/-, 29 C57B6 wild-type control (wt)] were used for in vivo experiments with intra-arterial and tail cuff blood pressure measurements. After perfusion fixation, kidneys were investigated with morphological, morphometric, stereological, and immunohistochemical techniques and TaqMan PCR analysis. As expected at this age, blood pressure was comparable between GDNF+/- and wt. Nephron number per kidney was significantly lower in GDNF+/- than in wt (-32.8%, P < 0.005), and mean glomerular volume was significantly higher (+49.5%, P < 0.001). Renal damage scores, glomerular and tubular proliferation, analysis of intrarenal arteries and peritubular capillaries, expression of relevant tubular transporter proteins, as well as gene expression of profibrotic, proinflammatory, or prohypertensive markers were not significantly different between GDNF+/- and wt. Compensatory glomerular hypertrophy in GDNF+/- was accompanied by higher numbers of endothelial and mesangial cells as well as PCNA-positive glomerular cells, whereas podocyte density was significantly reduced. Further electron microscopic analysis showed marked thickening of glomerular basement membrane. In conclusion, lower nephron number is associated with marked early glomerular structural changes, in particular lower capillary supply, reduced podocyte density, and thickened glomerular basement membrane, that may predispose to glomerular sclerosis. [ABSTRACT FROM AUTHOR]

Development of diabetic nephropathy is accompanied by changes in integrin-mediated cell-matrix interactions. The α8-integrin chain is specifically expressed in mesangial cells of the glomerulus. During experimental hypertension, α8-integrin plays a protective role in the glomerulus. We hypothesized that α8-integrin is involved in maintaining the integrity of the glomerulus in diabetic nephropathy. Experimental streptozotocin (STZ) diabetes led to an increased expression and glomerular deposition of α8-integrin. To test the functional role of α8-integrin, STZ diabetes was induced in mice with a homozygous (α8-/-) or heterozygous (α8+/-) deletion of the α8-integrin gene and in wild-type litters (α8+/+). Blood glucose and mean arterial blood pressure were not different in α8-/- and α8+/+ mice after 6 wk of diabetes. However, diabetic α8-/- mice developed significantly higher albuminuria and more glomerulosclerosis than diabetic α8+/+ mice. Moreover, in diabetic α8-/- mice, the number of glomerular cells staining positive for the podocyte markers WT-1 and vimentin were reduced more prominently than in diabetic α8+/+. The filtration barrier protein nephrin was downregulated in diabetic glomeruli with the strongest reduction observed in α8-/- mice. Taken together, α8-/- mice developed more severe glomerular lesions and podocyte damage after onset of STZ diabetes than α8+/+ mice, indicating that α8-integrin is protective for the structure and function of the glomerulus and maintains podocyte integrity during the development of diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Background: Extracellular matrix receptors of the integrin family are known to regulate cell adhesion, shape and functions. The α8 integrin chain is expressed in glomerular mesangial cells and in vascular smooth muscle cells. Mice deficient for α8 integrin have structural alterations in glomeruli but not in renal arteries. For this reason we hypothesized that mesangial cells and vascular smooth muscle cells differ in their respective capacity to compensate for the lack of α8 integrin. Results: Wild type and α8 integrin-deficient mesangial cells varied markedly in cell morphology and expression or localization of cytoskeletal molecules. In α8 integrin-deficient mesangial cells α-smooth muscle actin and CTGF were downregulated. In contrast, there were no comparable differences between α8 integrin-deficient and wild type vascular smooth muscle cells. Expression patterns of integrins were altered in α8 integrin-deficient mesangial cells compared to wild type mesangial cells, displaying a prominent overexpression of α2 and α6 integrins, while expression patterns of the these integrins were not different between wild type and α8 integrin-deficient vascular smooth muscle cells, respectively. Cell proliferation was augmented in α8 integrin-deficient mesangial cells, but not in vascular smooth muscle cells, compared to wild type cells. Conclusions: Our findings suggest that α8 integrin deficiency has differential effects in mesangial cells and vascular smooth muscle cells. While the phenotype of vascular smooth muscle cells lacking α8 integrin is not altered, mesangial cells lacking α8 integrin differ considerably from wild type mesangial cells which might be a consequence of compensatory changes in the expression patterns of other integrins. This could result in glomerular changes in α8 integrin-deficient mice, while the vasculature is not affected in these mice. [ABSTRACT FROM AUTHOR]

BackgroundIn the heart, the α8 integrin chain is expressed in fibroblasts and vascular smooth-muscle cells but its functional role in the myocardium is unknown. Integrins can contribute to tissue fibrosis in several organs. We tested the hypothesis that α8 integrin–mediated cell–matrix interactions add to cardiac fibrotic alterations during hypertension.MethodsDesoxycorticosterone-acetate (DOCA)-salt hypertension was induced in mice homozygous for a deletion of the α8 integrin chain and wild-type mice. Histological and immunohistochemical evaluations were performed in heart tissue.ResultsBlood pressure was slightly higher in DOCA-treated α8 integrin–deficient mice compared to DOCA-treated wild types. Expression of α8 integrin and its ligands fibronectin and osteopontin was increased in the hearts of DOCA-treated wild types compared to salt-loaded controls. However, relative left ventricular weights did not differ between DOCA-treated wild types and α8 integrin–deficient mice. Moreover, expansion of collagen I immunoreactivity and cell proliferation was similar in both groups. The number of osteopontin-positive cells was not different in DOCA-treated α8 integrin–deficient and DOCA-treated wild-type mice. Despite of a comparable degree of fibrosis in both groups, α-smooth-muscle actin and discoidin domain receptor 2 (DDR2)-positive myofibroblasts were only detected in wild-type DOCA-treated mice, not in DOCA-treated α8 integrin–deficient mice.ConclusionsThe results show that lack of α8 integrin does not reduce fibrotic changes in the hearts of DOCA-salt hypertensive mice. Our findings do not argue for a profibrotic effect of an increased α8 integrin expression in the myocardium in hypertension.American Journal of Hypertension (2009). doi:10.1038/ajh.2008.309American Journal of Hypertension (2009); 22, 1, 92–99. doi:10.1038/ajh.2008.309 [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) in angiotensin II (ANG II)-induced hypertension and target organ damage in mice. Mice transgenic for the human DDAH1 gene (TG) and wild-type (WT) mice (each, n = 28) were treated with 1.0 μg·kg-1·min-1 ANG II, 3.0 μg·kg-1·min-1 ANG II, or phosphate-buffered saline over 4 wk via osmotic minipumps. Blood pressure, as measured by tail cuff, was elevated to the same degree in TG and WT mice. Plasma levels of ADMA were lower in TG than WT mice and were not affected after 4 wk by either dose of ANG II in both TG and WT animals. Oxidative stress within the wall of the aorta, measured by fluorescence microscopy using the dye dihydroethidium, was significantly reduced in TG mice. ANG II-induced glomerulosclerosis was similar between WT and TG mice, whereas renal interstitial fibrosis was significantly reduced in TG compared with WT animals. Renal mRNA expression of protein arginine methyltransferase (PRMT)1 and DDAH2 increased during the infusion of ANG II, whereas PRMT3 and endogenous mouse DDAH1 expression remained unaltered. Chronic infusion of ANG II in mice has no effect on the plasma levels of ADMA after 4 wk. However, an overexpression of DDAH1 alleviates ANG II-induced renal interstitial fibrosis and vascular oxidative stress, suggesting a blood pressure-independent effect of ADMA on ANG II-induced target organ damage. [ABSTRACT FROM AUTHOR]

Liddle's syndrome is an autosomal dominant form of human hypertension, caused by gain-of-function mutations of the epithelial sodium channel (ENaC) which is expressed in aldosterone target tissues including the distal colon. We used a mouse model for Liddle's syndrome to investigate ENaC-mediated Na+ transport in late distal colon by measuring the amiloride-sensitive transepithelial short circuit current (Δ ISC-Ami) ex vivo. In Liddle mice maintained on a standard salt diet, Δ ISC-Ami was only slightly increased but plasma aldosterone (PAldo) was severely suppressed. Liddle mice responded to a low or a high salt diet by increasing or decreasing, respectively, their PAldo and Δ ISC-Ami. However, less aldosterone was required in Liddle animals to achieve similar or even higher Na+ transport rates than wild-type animals. Indeed, the ability of aldosterone to stimulate Δ ISC-Ami was about threefold higher in Liddle animals than in the wild-type controls. Application of aldosterone to colon tissue in vitro confirmed that ENaC stimulation by aldosterone was not only preserved but enhanced in Liddle mice. Aldosterone-induced transcriptional up-regulation of the channel's β- and γ-subunit (βENaC and γENaC) and of the serum- and glucocorticoid-inducible kinase 1 (SGK1) was similar in colon tissue from Liddle and wild-type animals, while aldosterone had no transcriptional effect on the α-subunit (αENaC). Moreover, Na+ feedback regulation was largely preserved in colon tissue of Liddle animals. In conclusion, we have demonstrated that in the colon of Liddle mice, ENaC-mediated Na+ transport is enhanced with an increased responsiveness to aldosterone. This may be pathophysiologically relevant in patients with Liddle's syndrome, in particular on a high salt diet, when suppression of PAldo is likely to be insufficient to reduce Na+ absorption to an appropriate level. [ABSTRACT FROM AUTHOR]

Background/Aims: α8β1-Integrin is expressed in mesangial cells. In vitro studies suggest a role for α8-integrin in the regulation of cell proliferation and apoptosis. We tested the hypothesis that α8-integrin is essential for the healing process after mesangioproliferative glomerulonephritis. Methods: Mice homozygous for a deletion of the α8-integrin chain were compared with wild-type mice. To study glomerular healing, we used the habu toxin model of reversible mesangioproliferative glomerulonephritis. Animals received 6 mg/kg habu toxin intravenously; controls received saline only. Results: Early mesangiolysis occurred in wild-type and α8-integrin-deficient mice. However, mesangiolysis was no longer detectable after 7 days in wild types but persisted after 14 days in α8-integrin-deficient animals. Mesangial activation marker α-smooth muscle actin was detectable only at day 7 in wild-type mice but persisted until day 14 in α8-integrin-deficient mice. In wild types, glomerular cell proliferation and apoptosis peaked at day 7 and decreased thereafter but remained elevated in α8-integrin-deficient mice until day 28. In cultivated mesangial cells, α8-integrin expression was associated with increased cell survival. Conclusion: Interactions between α8-integrin and the mesangial matrix may contribute to healing of glomerular injury by influencing cell proliferation and apoptosis. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

ln contrast to other sympathetic outflow tracts, renal sympathetic nerve activity (RSNA) decreases in response to hypotensive hemorrhage. The functional significance of this ‘paradox’ is not known. We tested the hypothesis that RSNA modulates renal perfusion and thus erythropoietin (EPO) release after transient hypotensive hemorrhage in anesthetized rats. Plasma EPO was measured before and after 30 mm of transient hypotensive hemorrhage (i.e., -40 mmHg from mean baseline blood pressure, followed by reinfusion of shed blood) and 120 mm thereafter in sham-denervated rats, and after renal denervation (DNX) or bilateral cervical vagotomy (VX) to abolish/blunt the RSNA decrease mediated by a cardiopulmonary reflex. RSNA, renal Doppler flow, renal vascular resistance (RVR), resistance index, and oxygen delivery/uptake (Do2/Vo2) were measured. RSNA decreased in intact animals (-40 ± 5% from baseline, P < 0.05). This was blunted by VX. With intact nerves, EPO level did not increase. In DNX rats, EPO was increased at minute 120 (49 ± 3 vs. 74 ± 2 mU/mi; P < 0.05), in VX rats this (47 ± 2 vs. 62 ± 4 mU/ml; P < 0.05) was less pronounced. Do2 in DNX rats was lower compared with intact and VX rats (0.25 ± 0.04 vs. 0.51 ± 0.06 and 0.54 ± 0.05 ml 02/min; P< 0.05) due to lower Doppler flow and increased RVR. RVR and Do2 were similar in intact and VX rats, but resistance index differed between all groups (0.70 ± 0.02 vs. 0.78 ± 0.02 vs. 0.85 ± 0.02; P < 0.05, intact vs. VX vs. DNX), indicating differential reactivity of renal vasculature. VO2 was unaffected by VX and DNX. Renal sympathoinhibition during hypotensive hemorrhage might help to preserve sufficient oxygenation of renal tissue by modulation of hemodynamic mechanisms that act to adapt renal oxygen availability to demand. [ABSTRACT FROM AUTHOR]

Background: The activity of the renin-angiotensin system influences blood pressure (BP) and cardiovascular structure in humans. Therefore, we questioned whether left-ventricular (LV) structure and function are influenced by the −20 A/C variant of the angiotensinogen (AGT) gene in young normotensive or mildly hypertensive patients. Methods: A homogenous cohort of young, male, white subjects (n = 214) with normal or mildly elevated BP never treated in the past, or on current cardiovascular medication, were recruited. All subjects were genotyped by single-strand conformational polymorphism analysis and DNA sequencing for the −20 A/C polymorphism of the AGT gene. Ambulatory BP was assessed over 24 h by an automatic portable device. Left-ventricular structure and function were determined by two-dimensional guided M-mode echocardiography. Results: The frequency of subjects homozygous for the −20 A allele was 73.4%, and the frequency for those with at least one copy of the −20 C allele was 26.6%. In hypertensive subjects with at least one copy of the −20 C allele, posterior (P = .027) and septal (P = .021) wall thickness, as well as LV mass (P = .027), were greater than in hypertensive subjects homozygous for the −20 A allele. Moreover, LV functional parameters such as midwall fractional fiber shortenings (P = .021) and the velocity of circumferential fiber shortening (P = .013) were decreased in hypertensive subjects with at least one copy of the −20 C allele, compared with subjects homozygous for the −20 A allele. Confounding factors of LV structure and systolic function, such as age, height, body mass index, physical activity, ambulatory 24-h BP, and sodium intake, were similar between the −20 A/C variants of the AGT gene in both normotensive and hypertensive subjects. Conclusions: In young, mildly hypertensive subjects, cardiac structure and function are modulated by the −20 A/C gene variant of the AGT. [Copyright &y& Elsevier]

The idea that an osmotically inactive Na+ storage pool exists that can be varied to accommodate states of Na+ retention and/or Na+ loss is controversial. We speculated that considerable amounts of osmotically inactive Na+ are lost with growth and that additional dietary salt excess or salt deficit alters the polyanionic character of extracellular glycosaminoglycans in osmotically inactive Na+ reservoirs. Six- week-old Sprague-Dawley rats were fed low-salt (0.1%; LS) or high-salt (8%; HS) diets for 1 or 4 wk. At their death, we separated the tissues and determined their Nat, K+, and water content. Three weeks of growth reduced the total body Na+ content relative to dry weight (rTBNa+) by 23%. This "growth-programmed" Na+ loss originated from the bone and the completely skinned and bone- removed carcasses. The Na+ loss was osmotically inactive (45-50%) or osmotically active (50-55%). In rats aged 10 wk, compared with HS, 4 wk of LS reduced rTBNa+ by 9%. This dietary-induced Na+ loss was osmotically inactive (≈50%) and originated largely from the skin, while ≈50% was osmotically active. LS for 1 wk did not reduce skin Na+ content. The mobilization of osmotically inactive skin Na+ with long-term salt deprivation was associated with decreased negatively charged skin glycosaminoglycan content and thereby a decreased water-free Na+ binding capacity in the extracellular matrix. Our data not only serve to explain discrepant results in salt balance studies but also show that glycosaminoglycans may provide an actively regulated interstitial cation exchange mechanism that participates in volume and blood pressure homeostasis. [ABSTRACT FROM AUTHOR]

The article discusses research regarding the renin-angiotensin system and cardiovascular risk. Experts say blockade of this system will produce strategies to reduce cardiovascular risk. Scientists say renin activity predicts cardiovascular events. Clinical studies have also shown that renin-angiotensin system blockade prevents or at least delays the onset of type 2 diabetes. There are several classes of drugs that inhibit the renin-angiotensin system available. ACE inhibitors and ARB drugs both have potential to protect patients from stroke. Researchers say further study into the renin-angiotensin system could produce novel therapeutic strategies.

Polymorphisms of the angiotensinogen (Agt) gene may affect blood pressure. We used a mouse model to test for the role of the Agt genotype in low-renin or high-renin forms of hypertension. Mice bearing one, two, three, or four copies of the Agt gene underwent renal artery clipping to induce high-renin two-kidney, one-clip renovascular hypertension (2K1C), or uninephrectomy, salt loading, and application of deoxycorticosterone-acetate (DOCA) pellets to induce low-renin mineralocorticoid hypertension. Appropriate control animals were also studied. Blood pressure was measured by tail cuff as well as by direct intra-arterial recordings. There was a small effect of the Agt genotype on baseline blood pressure before induction of hypertension. The extent of 2K1C hypertension was not affected by the genotype. In contrast, there was a marked gene-dose effect on DOCA-hypertension (21.2 mmHg over all genotypes). Treatment of DOCA mice with the angiotensin II type 1 receptor antagonist abolished the genotype effect on blood pressure and left ventricular hypertrophy. There was a trend towards less suppression of endogenous aldosterone by DOCA treatment with increasing number of Agt gene copies. We conclude that the Agt genotype exerts a marked effect on blood pressure in a low-renin form of hypertension but no effect in the face of stimulated renin, at least in mice. [ABSTRACT FROM AUTHOR]

lnduction of streptozotocin (STZ) diabetes in hypertensive rats transgenic for the mouse ren-2 gene (TOR) has been described as a model of progressive diabetic nephropathy. We investigated the long-term course of STZ diabetes in TGR and appropriate Sprague-Dawley control rats (SD) and tested the role of angiotensin-dependent hypertension by treating rats with the angiotensin if type 1 receptor blocker losartan (1 mg·kg-1·day-1) via osmotic minipumps. Five weeks after STZ injection, diabetes developed in TGR and SD. Urinary albumin excretion was increased by diabetes and, to a much higher degree, by hypertension. The effects of hypertension and diabetes were not additive, and only the effects of hypertension were ameliorated by losartan. A similar pattern was observed for cell proliferation and macrophage infiltration in the kidney. In contrast, the effects of hypertension and diabetes on glomerular collagen IV accumulation were additive 5 wk after STZ injection. In a long-term study for 20 wk after STZ, survival was better in STZ-treated TOR than in normoglycemic TGR, whereas all SD survived, Impaired creatinine clearance and increased macrophage infiltration as well as glomerular and interstitial matrix deposition were prominent in TGR compared with SD, regardless of the presence or absence of diabetes. In conclusion, STZ diabetes in TGR may be useful to study glomerular and interstitial matrix deposition early in the course of diabetes. However, the long-term course of this animal model resembles severe hypertensive nephrosclerosis, rather than progressive diabetic nephropathy. [ABSTRACT FROM AUTHOR]

The microfibrillar protein fibrillin-1 is a component of the mesangial matrix. Defects in fibrillin-1 predisposes individuals to vascular damage in Marfan syndrome, but the role of fibrillin-1 in kidney disease is unknown. We hypothesized that fibrillin-1 is involved in hypertensive or diabetic glomerular disease. DOCA-salt hypertension or streptozotocin (STZ) diabetes led to a significant increase in glomerular fibrillin-1 deposition. To test the functional role of fibrillin-1, DOCA hypertension and STZ diabetes were induced in mice homozygous for a mutation leading to a fivefold lower expression of fibrillin-1 (mgR/mgR). Untreated male mgR/mgR mice usually die from aortic dissection during the first 4 mo of life. All DOCA-treated mgR/mgR mice died within 2 wk after onset of DOCA treatment. DOCA-treated heterozygous (mgR/+) and their wild-type littermates displayed similar blood pressure levels, but albuminuria was significantly lower in mgR/+ than in wild-type mice after DOCA treatment. Similarly, STZ diabetic mgR/mgR and mgR/+ developed lower albuminuria than wild-type mice despite higher blood glucose levels in mgR/mgR and mgR/+ compared with wild-type mice. Blood pressure, blood glucose, and albuminuria did not differ among untreated mgR/mgR, mgR/+, and wild-type mice, respectively. In diabetic mgR/+ and mgR/mgR, but not in wild-type mice, an induction of glomerular decorin expression was observed. Thus underexpression of fibrillin-1 predisposes individuals to lethal aortic dissection in the presence of hypertension. On the other hand, albuminuria as a parameter of microvascular damage in hypertension and diabetes was ameliorated in fibrillin-1-underexpressing mice, possibly clue to a compensatory upregulation of decorin. We conclude that fibrillin-1 may contribute to glomerular damage in hypertensive and diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Renal and preganglionic adrenal sympathetic nerve activities (RSNA, ASNA) are regulated differentially. Various cardiopulmonary receptor (CPR) stimulation procedures were performed to distinguish short–term and prolonged as well as mechanical and chemical stimulatory effects on RSNA and ASNA. In anesthetized male Sprague–Dawley rats blood pressure, heart rate, left ventricular end–diastolic pressure (LVEDP), RSNA and ASNA were recorded. CPRs were stimulated as follows: Short–term mechanical: LVEDP changes (±4, ±6, ±8 mmHg) via aortic and caval vein occlusion; Short–term chemical: phenylbiguanide (PBG–bolus, 0.1, 1, 10 µg IV); Prolonged mechanical (15 min): volume expansion (0.9% NaCl, 5% body weight) and hemorrhage, to modulate LVEDP; Prolonged chemical: PBG infusion (32 µg/min IV, for 15 min); Stimulations were done with 1) all afferents intact, 2) bilateral cervical vagotomy (VX), 3) VX + SAD (sino–aortic denervation; short–term protocols and hemorrhage). 1) Short–term mechanical stimuli decreased RSNA (–52 ± 12%) and ASNA (–37 ± 13%). 2) PBG–bolus decreased RSNA (–54 ± 12%) but increased ASNA (+40 ± 13%). 3) Volume expansion decreased RSNA (–55 ± 7%), ASNA was unaffected. 4) PBG infusion persistently decreased RSNA (–60 ± 6%) but just shortly increased ASNA (+120 ± 15%); VX abolished all responses. 5) Hypotensive hemorrhage decreased RSNA (–39 ± 9%) but increased ASNA (+42 ± 9%). VX abolished RSNA response; ASNA response only disappeared with VX + SAD. Short–term mechanical CPR stimulation uniformly decreased sympathetic activities, whereas chemical stimulation had opposing effects on renal and adrenal sympathetic responses. All prolonged stimuli decreased RSNA, whereas ASNA was virtually unaffected: Sympathetic out.ow is differentially controlled not only with regard to target organs or afferent receptors but also stimulus time pattern. [ABSTRACT FROM AUTHOR]

The idea that Na+ retention inevitably leads to water retention is compelling; however, were Na+ accumulation in part osmotically inactive, regulatory alternatives would be available. We speculated that in DOCA-salt rats Na+ accumulation is excessive relative to water. Forty female Sprague-Dawley rats were divided into four subgroups. Groups 1 and 2 (controls) received tap water or 1% saline (salt) for 5 wk. Groups 3 and 4 received subcutaneous DOCA pellets and tap water or salt. Na+, K+, and water were measured in skin, bone, muscle, and total body by desiccation and consecutive dry ashing. DOCA-salt led to total body Na+ excess (0.255 ± 0.022 vs. 0.170 ± 0.010 mmol/g dry wt; P « 0.001 ), whereas water retention was only moderate (0.685 + 0.119 vs. 0.648 ± 0.130 mug wet wt; P « 0.001). Muscle Na+ retention (0.220 ± 0.029 vs. 0.145 ± 0.021 mmol/g dry wt; P « 0.01) in DOCA-salt was compensated by muscle K+ loss, indicating osmotically neutral Na+/K+ exchange. Skin Na+ retention (0.267 ± 0.049 vs. 0.152 ± 0.014 mmol/g dry wt; P « 0.001) in DOCA-salt rats was not balanced by K+ loss, indicating osmotically inactive skin Na+ storage. We conclude that DOCA-salt leads to tissue Na+ excess relative to water. The relative Na+ excess is achieved by two distinct mechanisms, namely, osmotically inactive Na+ storage and osmotically neutral Na+ retention balanced by K+ loss. This ‘internal Na+ escape’ allows the maintenance of volume homeostasis despite increased total body Na+. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that angiotensin II is likely to be mandatory for the neurogenic sodium and volume retention in cirrhotic rats with common bile duct ligature (BDL) following an acute volume load. To assess the neural control of volume homeostasis, 21 days after common BDL rats underwent volume expansion (0.9% NaCL; 10% body wt over 30 mm) to decrease renal sympathetic nerve activity. Untreated animals, rats with renal denervation or pretreated with a nonhypotensive dose of an angiotensin II type I receptor antagonist were studied. The renal renin-angiotensin system was assessed by immunohistochemistry and RT-PCR. Rats with BDL excreted only 71 ± 4% of the administered volume load. In cirrhotic rats pretreated with an angiotensin II AT1 inhibitor or after renal denervation, these values ranged significantly higher from 98 to 103% (P < 0.05 for all comparisons). Renal sympathetic nerve activity decreases by volume expansion were impaired in BDL rats (P < 0.05) but unaffected by angiotensin II receptor inhibition. In kidneys of BDL animals, renin mRNA was increased, and immunohistochemistry revealed increased staining for peritubular angiotensin II. Renal denervation in BDL animals reduced renin expression within 5 days to control levels. In conclusion, the impaired excretion of an acute volume load in rats with liver cirrhosis is due to effects of an increased renal sympathetic nerve activity that are likely to be dependent on intrarenal angiotensin II and renin. We speculate that similar changes may contribute to long-term volume retention in liver cirrhosis. [ABSTRACT FROM AUTHOR]

Left ventricular (LV) end-diastolic pressure (LVEDP) increase due to volume expansion (VExp) enhances mechanosensitive vagal cardiac afferent C-fiber activity (CNFA), thus ,decreasing renal sympathetic nerve activity (RSNA). Hypotensive hemorrhage (hHem) attenuates RSNA despite decreased LVEDP. We hypothesized that CNFA increases with any change in LVEDP. Coronary perfusion pressure (CPP), supposedly affected in both conditions, might also be a stimulus of CNFA. VExp and hHem were performed in anesthetized male Sprague-Dawley rats while blood pressure, heart rate, and RSNA were measured. Cervical vagotomy abolished RSNA response in both reflex responses. Single-unit CNFA was recorded while LVEDP was changed. Rapid changes (± 4, ±6, ±8 mmHg) were obtained by graded occlusion of the caval vein and descending aorta. Prolonged changes were obtained by VExp and hHem. Furthermore, CNFA was recorded in a modified Langendorff heart while CPP was changed (70, 100, 40 mmHg). Rapid LVEDP changes increased CNFA [caval vein occlusion: +16 ± 3 Hz (approximately +602%); aortic occlusion: +15 ± 3 Hz (approximately +553%); 70 units; P < 0.05]. VExp and hHem (n = 6) increased CNFA [VExp: +10 ± 4 Hz (approximately +1,033%); hHem: +10 ± 2 Hz (approximately +1,225%); P < 0.05]. An increase in CPP increased CNFA [+2 ± 1 Hz (approximately +225%); P < 0.05], whereas a decrease in CPP decreased CNFA [-0.8 ± 0.4 Hz (approximately -50%); P < 0.05]. All C fibers recorded originated from the LV. CNFA increased with any LVEDP change but changed equidirectionally with CPP. Thus neither LVEDP nor CPP fully accounts directly for afferent C-fiber and reflex sympathetic responses. The intrinsic afferent stimuli and receptive fields accounting for reflex sympathoinhibition still remain cryptic. [ABSTRACT FROM AUTHOR]

The microfibrillar protein fibrillin-1 is expressed abundantly in the vasculature and the glomerulus of the kidney. Mutations in the fibrillin-1 gene lead to Marfan syndrome. The most common complication of this disease is aortic dilatation due to elastic deficiencies of the vascular wall. Several case reports describe glomerular disease in patients with Marfan syndrome, and fibrillin-1 has been implicated in nephrogenesis. To study the role of fibrillin-1 in renal development and function, we characterized the renal phenotype of fibrillin-1-underexpressing mice. Kidney histology was evaluated by means of morphometry and stereology. Relative kidney weights, daily urine excretion, urinary albumin excretion, serum and urinary creatinine, as well as serum urea were not different than wild-type mice. Glomerular number and renal capillarization were normal. The size of the renal filtration surface was comparable in wild-type and fibrillin-1-underexpressing mice. There was no indication for glomerular, renal vascular, or tubulointerstitial injury. However, glomerular volume and mesangial area were reduced. No changes in glomerular cell numbers were detected, but the cellular volume of mesangial cells was significantly lower in glomeruli of fibrillin-1-underexpressing mice. Thus, despite the high abundance of fibrillin-1 in glomeruli of wild-type animals, underexpression of fibrillin-1 did not lead to functional deficiencies of the glomerulus. Alterations in renal histology were only subtle with a reduced glomerular volume and mesangial area likely due to a reduced mesangial cell volume. [ABSTRACT FROM AUTHOR]

We discuss the evidence supporting the use of angiotensin-converting enzyme inhibitors (ACEI), angiotensin II type 1 receptor blockers (ARB), or the combination of both in children with chronic renal disease. Several large-scale, prospective, randomized studies with clinical end points have been performed in adult patients, but studies in children are relatively scarce. In adult patients with chronic renal diseases, ACEI clearly delay the progression of chronic non-diabetic renal diseases, and nephropathy in patients with type 1 diabetes. The benefits of ACEI are most apparent in glomerular diseases with marked proteinuria but extend also to kidney diseases with lower proteinuria. This notion is also supported by several smaller or retrospective trials in children. Therefore, ACEI should be given to children with chronic renal diseases, particularly if high blood pressure and/or proteinuria are present. In adults, large-scale trials have documented that ARB exert similar effects as ACEI but tend to exert fewer undesired side effects. Data on ARB in children with chronic renal disease are still very scarce, but these substances offer an alternative for patients who cannot tolerate ACEI due to unwarranted side effects. Combination therapy with ARB plus ACEI may be more effective than either drug class alone. However, we will need the results of further long-term prospective clinical studies, as well as a better understanding of the role of the AT2 receptor, before combination therapy can be widely recommended. A trial of ARB plus ACEI is justified in selected patients if blood pressure and/or proteinuria cannot adequately be lowered by ACEI or ARB alone. [ABSTRACT FROM AUTHOR]

Osmotically inactive skin Na+ storage is characterized by Na+ accumulation without water accumulation in the skin. Negatively charged glycosaminoglycans (GAGs) may be important in skin Na+ storage. We investigated changes in skin GAG content and key enzymes of GAG chain polymerization during osmotically inactive skin Na+ storage. Female Sprague-Dawley rats were fed a 0.1% or 8% NaC1 diet for 8 wk. Skin GAG content was measured by Western blot analysis, mRNA content of key dermatan sulfate polymerization enzymes was measured by real-time PCR. The Na+ concentration in skin was determined by dry ashing. Skin Na+ concentration during osmotically inactive Na+ storage was 180-190 mmol/1. Increasing skin Na+ coincided with increasing GAG content in cartilage and skin. Dietary NaC1 loading coincided with increased chondroitin synthase mRNA content in the skin, whereas xylosyl transferase, biglycan, and decorin content were unchanged. We conclude that osmotically inactive skin Na+ storage is an active process characterized by an increased GAG content in the reservoir tissue. Inhibition or disinhibition of GAG chain polymerization may regulate osmotically inactive Na+ storage. [ABSTRACT FROM AUTHOR]

Compared with age-matched men, women are resistant to the hypertensive effects of dietary NaCl; however, after menopause, the incidence of salt-sensitive hypertension is similar in women and men. We recently suggested that osmotically inactive Na[sup +] storage contributes to the development of salt-sensitive hypertension. The connective tissues, including those immediately below the skin that may serve as a reservoir for osmotically inactive Na[sup +] storage, are affected by menopause. We tested the hypothesis that ovariectomy (OVX) might reduce osmotically inactive Na[sup +] storage capacity in the body, particularly in the skin. Male, femalefertile, and female OVX Sprague-Dawley (SD) rats were fed a high (8%)- or low (0.1%)-NaCl diet. The groups received the diet for 4 or 8 wk. At the end of the experiment, subgroups received 0.9% saline infusion and urinary Na[sup +] and K[sup +] excretion was measured. Wet and dry weight (DW), water content in the body and skin, total body Na[sup +] (rTBNa[sup +]) and skin Na[sup +] (rSKNa[sup +]) content were measured relative to DW by desiccation and dry ashing. There were no gender differences in osmotically inactive Na[sup +] storage in SD rats. All SD rats accumulated Na[sup +] if fed 8% NaCl, but rTBNa[sup +] was lower in OVX rats than in fertile rats on a low (P < 0.001)- and a high (P < 0.05)-salt diet. OVX decreased rSKNa[sup +] (P < 0.01) in the rats. A high-salt diet led to Na[sup +] accumulation (ΔSKNa[sup +]) in the skin in all SD rats. Osmotically inactive skin Na[sup +] accumulation was ∼66% of ΔSKNa[sup +] in female and 82% in male-fertile rats, but there was no osmotically inactive Na[sup +] accumulation in OVX rats fed 8% NaCl. We conclude that skin is an osmotically inactive Na[sup +] reservoir that accumulates Na[sup +] when dietary NaCl is excessive. OVX leads to an acquired reduction of osmotically inactive Na[sup +] storage in SD rats that predisposes the rats to volume excess despite a reduced Na[sup +] content relative to body weight. [ABSTRACT FROM AUTHOR]

Recent studies suggest a role of ion channels of the DEG/ENaC family for mechanosensation in different species and in baroreceptor reflex control in rats. We tested the hypothesis that ENaC within the cardiac sensory network are mandatory for mechanosensation. Experiments were performed in male Sprague-Dawley rats, isolated nodose ganglion cells with cardiac afferents and isolated vagus nerves. Epicardial delivery of the amiloride analogue benzamil intended to specifically inhibit ENaC presumably located on cardiac sensory afferents indeed blunted the mechanosensitive (i. e., sympathoinhibition by intravenous volume loading [–32% and –42% in treated groups vs. –67% in controls; n = 7 each; p < 0.05]) as well as—though to a lesser extent—the 5-HT3-mediated chemosensitive cardiorenal reflex in vivo in a dose-dependent manner. Using patch clamp technique, however, it turned out that neither amiloride nor benzamil influenced mechanically induced currents in ganglion nodosum cells in vitro, stimulated by hypoosmotic stress. The unspecific stretch activated ion channel blocker gadolinium completely abolished mechanically induced currents, indicating respective cells were mechanosensitive. In isolated vagus nerves benzamil impaired action potentials obtained by electrical stimulation (C-spike amplitude [–33%]; latency [+12%]; n = 8; p < 0.05). Our findings at least cast doubt on ENaC exclusively playing a specific role as mechanotransducers within the cardiac sensory network. Other ion channels might be involved. Furthermore the observed findings in vivo could also be due to unspecific disturbance of afferent signal conduction. [ABSTRACT FROM AUTHOR]

Vagal afferent C-fibres from the heart constitute an important input to the neurogenic cardiovascular regulation. These fibres respond to altered cardiac filling pressures and to chemical stimuli. In rats, we tested whether cardiac vagal afferent C-fibres react exclusively to one stimulus (chemical or mechanical) or whether the fibres are bimodal, i.e. responsive to either kind of stimulus. As a mechanical stimulus, an indwelling balloon was inflated in the aorta to increase left ventricular end-diastolic pressure. The serotonin 5HT3 receptor agonist phenylbiguanide was injected into the pericardial sac as a chemical stimulus. An increase of fibre activity by more than two standard deviations compared with control was considered a response to a stimulus. Most fibres (42 out of 57) responded to both stimuli and were categorized as bimodal, 9 fibres were solely mechanosensitive and 6 were solely chemosensitive. Hence, the majority of cardiac vagal C-fibres are likely to be bimodal, responding to both cardiac filling pressure and serotonin 5HT3 receptor stimulation. Our results emphasize the potential role of endogenous mediators in the afferent limb of cardiac reflexes. [ABSTRACT FROM AUTHOR]

Upregulation of the inducible cyclooxygenase (COX-2) in the macula densa accompanies the activation of the juxtaglomerular apparatus in many high-renin conditions. The functional role of COX-2 in these disease states is poorly understood. We tested whether COX-2 is required to increase renin in renovascular hypertension. Rats with established two-kidney, one-clip (2KIC) hypertension were treated for 2 wk with two different inhibitors of COX-2. NS-398 and rofecoxib, respectively. Hypertension in 2K1C rats was not affected or slightly enhanced by COX-2 inhibition, as measured intra-arterially in conscious animals. The increase in plasma renin activity was also unchanged by both rofecoxib and NS-398. The number of glomeruli with a renin-positive juxtaglomerular apparatus was elevated in clipped kidneys and decreased in contralateral kidneys of 2K1C rats. This pattern was unaltered by COX-2 inhibition. To test the effects of COX-2 blockade on a primarily macula densa-mediated stimulus, we studied salt depletion for comparison. A low-salt diet induced a significant increase m plasma renin activity, which was partially inhibited by treatment with NS-398. We conclude that inhibition of COX-2 in established renovascular hypertension does not affect renin synthesis or release. Thus either COX-2 is not necessary for the macula densa mechanism or the macula densa is not important for maintaining high renin in renovascular hypertension. [ABSTRACT FROM AUTHOR]

Numerous studies have demonstrated the involvement of the transforming growth factor (TGF) isoform β1 in the pathogenesis of renal fibroproliferative diseases. Although in vitro studies suggest that TGF-β2 is equally potent to TGF-β1 in terms of its antimitogenic and fibrogenic effects, much less is known about the regulation of TGF-β2 in renal diseases associated with glomerular cell hyperplasia and matrix expansion. Here we investigated the glomerular expression patterns of TGF-β2 and of the TGF-β receptors I, II, and III during the course of rat anti-Thy1.1 nephritis (days 2, 6, 12, and 56), a model characterized by transient mesangial hypercellularity and extracellular matrix accumulation. TGF-β2 exhibited dynamic changes in expression. Immunohistochemical double-staining of renal sections revealed that most TGF-β2-positive cells in control glomeruli were podocytes with few TGF-β2-positive mesangial cells. This staining pattern could also be observed in human kidney. On day 6 of anti-Thy1.1 nephritis both TGF-β2 positive podocytes and mesangial cells were more abundant. By western blot analysis of isolated glomeruli from nephritic rats, protein expression of TGF-β2 was upregulated tenfold over control glomeruli, peaking on day 6 of the disease. In cultured rat mesangial cells we found that the TGF-β2 and TGF-β1 isoforms were equally potent in terms of nuclear accumulation of phosphorylated Smad 2/3, inhibition of DNA synthesis, and induction of β1-integrin and type I collagen protein synthesis. Protein expression of the TGF-β receptor I was not detected by immunohistochemistry in control glomeruli but was markedly induced in the mesangium on day 6 of nephritis. Mesangial staining for TGF-β receptors II and III was detected in normal kidneys. Expression of TGF-β receptor II was strongly enhanced on days 6 and 12 of disease, while TGF-β receptor III was upregulated only on day 6. In summary, we report marked yet transient upregulation of TGF-β2 protein and of TGF-β receptors I, II, and III in glomerular cells during anti-Thy1.1 nephritis. These results are in keeping with the notion that TGF-β2 and its receptors participate in the pathogenesis and/or resolution of this transient form of glomerulonephritis. [ABSTRACT FROM AUTHOR]

Examines the reduction of osmotically inactive sodium (NA) storage capacity and hypertension in the rat model. Relationship between salt intake and blood pressure; Identification of sodium and water distribution in high-dietary Na consumption; Impact of hypertension on the impairement of renal sodium excretion.

Presents letters to the editor on topics in medicine as of May 11, 2002. Renoprotection with anti-hypertensive agents; International normalized ratio and liver impairment; Vitamin B12 deficiency; Early assessment of anti-HIV drug efficacy; Others.

Monocyte chemoattractant protein-1 and macrophage infiltration in hypertensive kidney injury. Background. We investigated whether monocyte chemoattractant protein-1 (MCP-1) is expressed in hypertensive nephrosclerosis, and tested the effect of angiotensin II type 1 receptor blockade on MCP-1 expression and macrophage (MΦ) infiltration. Methods. Rats with two-kidney, one-clip (2K1C) hypertension with and without treatment with the angiotensin II type 1 receptor antagonist valsartan (3 mg/kg/day) were studied. In these animals as well as in spontaneously hypertensive rats (SHR), stroke-prone SHR (SHR-SP), hypertensive mRen-2 transgenic rats (TGR), and respective control strains, MCP-1 expression in the kidney was investigated by Northern and Western blots and by immunohistochemistry. Glomerular and interstitial MΦs were counted. Results. In the nonclipped kidney of 2K1C rats, MCP-1 expression was elevated at 14 and 28 days when significant MΦ infiltration was present. MCP-1 was localized to glomerular endothelial and epithelial cells, interstitial and tubular cells, MΦs, and vascular smooth muscle cells. A similar pattern of MCP-1 staining was present in TGR kidneys, whereas MCP-1 expression was not increased in SHR and SHR-SP. Valsartan reduced but did not normalize blood pressure, blocked the induction of MCP-1 protein in 2K1C kidneys, and decreased interstitial MΦ infiltration significantly. Conclusion. MCP-1 expression is increased in angiotensin II-dependent models of hypertensive nephrosclerosis and is temporally and spatially related to MΦ infiltration. The angiotensin II type 1 receptor mediates the induction of MCP-1. [ABSTRACT FROM AUTHOR]

Studies the possible role of cardiopulmonary reflexes in control of volume homeostasis. Regulation of the renal sympathetic nerve activity with subthreshold stimulation of serotonin 5-HT3 receptors; Phenyl biguanide infusion; Effects on volume retention when cardiac serotonin is increased.

Tests the hypothesis that local vascular formation of angiotensin II and the sympathetic nervous system potentiate each other. Hindquarter perfusion; Nerve stimulation; Experimental protocols.

Background: We aimed to identify genes with kidney specific, developmentally regulated expression. Here we report the cDNA sequence and expression pattern of KS, a novel kidney-specific rat gene.Methods: A partial cDNA was identified by differential display polymerase chain reaction (PCR) of a renal cell fraction enriched for proximal tubular and renin-expressing cells. Using the partial cDNA as a probe, a rat kidney cDNA library was screened. The full-length KS sequence was obtained by PCR amplification of cDNA ends. The expression pattern of KS was investigated by Northern blot. RNA was extracted from several organs of newborn and adult rats, as well as from the kidneys of rats with altered tubular function, that is, rats that had undergone unilateral nephrectomy, unilateral ureteral obstruction, neonatal losartan treatment, and the appropriate control animals. The expression of KS was also investigated in the kidneys of rats with spontaneous or renovascular hypertension.Results: The KS cDNA (2426 bp) contained one open reading frame encoding a predicted 572 amino acid protein. The derived peptide sequence displayed approximately 70% similarity to the hypertension-related SA gene product and approximately 50% similarity to prokaryotic and eukaryotic acetyl-CoA synthases (EC 6. 2.1.1). KS was expressed in the kidney and not in any other organ assayed. KS RNA was not detected in fetal and newborn rat kidney but became apparent after one week of postnatal life. Gene expression was downregulated in rat models of altered tubular function. KS expression was decreased in spontaneously hypertensive rats but not in renovascular hypertension.Conclusion: KS, a novel rat gene, exhibits a unique tissue-specific expression exclusively in mature kidneys. The data suggest KS may encode an adenosine monophosphate binding enzyme. [ABSTRACT FROM AUTHOR]