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BACKGROUND: Autosomal recessive renal tubular dysgenesis is a rare, usually fatal inherited disorder of the renin-angiotensis system (RAS). Herein, we report an adolescent individual experiencing an unknown chronic kidney disease and aim to provide novel insights into disease mechanisms. METHODS: Exome sequencing for a gene panel associated with renal disease was performed. The RAS was assessed by comprehensive biochemical analysis in blood. Renin expression was determined in primary tubular cells by quantitative polymerase chain reaction and in situ hybridization on kidney biopsy samples. Allele frequencies of heterozygous and biallelic deleterious variants were determined by analysis of the Genomics England 100,000 Genomes Project. RESULTS: The patient was delivered prematurely after oligohydramnios was detected during pregnancy. Postnatally, he recovered from third-degree acute kidney injury but developed chronic kidney disease stage G3b over time. Exome sequencing revealed a previously reported pathogenic homozygous missense variant, p.(Arg375Gln), in the AGT (angiotensinogen) gene. Blood AGT concentrations were low, but plasma renin concentration and gene expression in kidney biopsy, vascular, and tubular cells revealed strong upregulation of renin. Angiotensin II and aldosterone in blood were not abnormally elevated. CONCLUSIONS: Renal tubular dysgenesis may present as chronic kidney disease with a variable phenotype, necessitating broad genetic analysis for diagnosis. Functional analysis of the RAS in a patient with AGT mutation revealed novel insights regarding compensatory upregulation of renin in vascular and tubular cells of the kidney and in plasma in response to depletion of AGT substrate as a source of Ang II (similarly observed with hepatic AGT silencing for the treatment of hypertension). [ABSTRACT FROM AUTHOR]

During nephrogenesis, renin expression shifts from the vessel walls of interlobular arteries to the terminal portions of afferent arterioles in a wavelike pattern. Since the mechanisms responsible for the developmental deactivation of renin expression are as yet unknown, we hypothesized that the developing renin-angiotensin system (RAS) may downregulate itself via negative feedback to prevent overactivity of renin. To test for a possible role of angiotensin II in the developmental deactivation of renin expression, we studied the development of intrarenal renin expression in mice lacking ANG II [AT.sub.1a], [AT.sub.1b], or [AT.sub.2] receptors and in animals with abolished circulating ANG II due to deletion of the gene for angiotensin I-converting enzyme (ACE). The development of intrarenal renin expression was normal in mice lacking ANG II [AT.sub.1b] or [AT.sub.2] receptors. In animals lacking both ANG II [AT.sub.1a] and [AT.sub.1b] receptors, ACE, or ANG II [AT.sub.1a] receptors, renin expression was normal early and renin disappeared from mature vessels until development of cortical interlobular and afferent arterioles began. The development of cortical vessels in these genotypes was accompanied by a markedly increased number of renin-expressing cells, many of which were ectopically located and attached in a grapelike fashion to the outer vessel perimeter. Although the number of renin-expressing cells declined during final maturation of the kidneys, the atypical distribution pattern of renin cells was maintained. These findings suggest that ANG II does not play a central role in the typical developmental shift in renin expression from the arcuate vessels to the afferent arterioles. During postnatal maturation of mouse kidneys, interruption of the RAS causes severe hyperplasia of renin cells via a mechanism that centrally involves [AT.sub.1a] receptors. However, the distribution pattern of renin cells in adult kidneys with an interrupted RAS does not mimic any normal developmental stage since renin expression is frequently found in cells outside the arteriolar vessel walls in RAS mutants. development; angiotensin II doi: 10.1152/ajprenal.00378.2009.

In salt-sensitive hypertension, the accumulation of [Na.sup.+] in tissue has been presumed to be accompanied by a commensurate retention of water to maintain the isotonicity of body fluids. We show here that a high-salt diet (HSD) in rats leads to interstitial hypertonic Na+ accumulation in skin, resulting in increased density and hyperplasia of the lymphcapillary network. The mechanisms underlying these effects on lymphatics involve activation of tonicity-responsive enhancer binding protein (TonEBP) in mononuclear phagocyte system (MPS) cells infiltrating the interstitium of the skin. TonEBP binds the promoter of the gene encoding vascular endothelial growth factor-C (VEGF-C, encoded by Vegfc) and causes VEGF-C secretion by macrophages. MPS cell depletion or VEGF-C trapping by soluble VEGF receptor-3 blocks VEGF-C signaling, augments interstitial hypertonic volume retention, decreases endothelial nitric oxide synthase expression and elevates blood pressure in response to HSD. Our data show that TonEBP-VEGF-C signaling in MPS cells is a major determinant of extracellular volume and blood pressure homeostasis and identify VEGFC as an osmosensitive, hypertonicity-driven gene intimately involved in salt-induced hypertension., Hypertension is the major risk factor for cardiovascular disease. HSD is implicated in hypertension; however, the sensitivity of blood pressure to salt among individuals is variable, and the mechanisms for [...]

[Na.sup.+] loading without [Cl.sup.-] fails to increase blood pressure in the DOCA model. We compared the changes in the total body (TB) effective [Na.sup.+], [K.sup.+], [Cl.sup.-] , and water (TBW) content as well as in intracellular (ICV) or extracellular (ECV) volume in rats receiving DOCA-NaCl, DOCA-NaHC[O.sub.3], or DOCA-KHC[O.sub.3]. We divided 42 male rats into 5 groups. Group 1 was untreated, group 2 received 1% NaCl, and groups 3, 4, and 5 were treated with DOCA and received 1% NaCl, 1.44% NaHC[O.sub.3], or 1.7% KHC[O.sub.3] to drink. We measured mean arterial blood pressure (MAP) directly after 3 wk. Tissue electrolyte and water content was measured by chemical analysis. Compared with control rats, DOCA-NaCl increased MAP while DOCA-NaHC[O.sub.3] and DOCA-KHC[O.sub.3] did not. DOCA-NaCl increased TB[Na.sup.+] 26% but only moderately increased TBW. DOCA-NaHC[O.sub.3] led to similar TB[Na.sup.+] excess, while TBW and ICV, but not ECV, were increased more than in DOCA-NaCl rats. DOCA-KHC[O.sub.3] did not affect TB[Na.sup.+] or volume. At a given TB([Na.sup.+] + [K.sup.+]) and TBW, MAP in DOCA-NaCl rats was higher than in control, DOCA-NaHC[O.sub.3], and DOCA-KHC[O.sub.3] rats. indicating that hypertension in DOCA-NaCl rats was not dependent on TB([Na.sup.+] + [K.sup.+]) and water mass balance. Skin volume retention was hypertonic compared with serum and paralleled hypertension in DOCA-NaCl rats. These rats had higher TB([Na.sup.+] + [K.sup.+])-to-TBW ratio in accumulated fluid than DOCA-NaHC[O.sub.3] rats. DOCA-NaCl rats also had increased intracellular [Cl.sup.-] concentrations in skeletal muscle. We conclude that excessive cellular electrolyte redistribution and/or intracellular [Na.sup.+] or [Cl.sup.-] accumulation may play an important role in the pathogenesis of salt-sensitive hypertension. DOCA-salt; salt-induced hypertension; autoregulation; osmotically inactive sodium

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 tyansgenic for the human DDAH1 gene (TG) and wild-type (WT) mice (each, n = 28) were treated with 1.0 [micro]g*[kg.sup.-1]* [min.sup.-1] ANG II, 3.0 [micro]g*[kg.sup.-1]*[min.sup.-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)I 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 al|eviates 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. dimethylarginine dimethylaminohydrolase; hypertension; transgenic

In 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 min of transient hypotensive hemorrhage (i.e., -40 mmHg from mean baseline blood pressure, followed by reinfusion of shed blood) and 120 min 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 ([DO.sub.2]/[[??]O.sub.2]) were measured. RSNA decreased in intact animals (-40 [+ or -] 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 [+ or -] 3 vs. 74 [+ or -] 2 mU/ml; P < 0.05), in VX rats this (47 [+ or -] 2 vs. 62 [+ or -] 4 mU/ml; P < 0.05) was less pronounced. [DO.sub.2] in DNX rats was lower compared with intact and VX rats (0.25 [+ or -] 0.04 vs. 0.51 [+ or -] 0.06 and 0.54 [+ or -] 0.05 ml [O.sub.2]/min; P < 0.05) due to lower Doppler flow and increased RVR. RVR and [DO.sub.2] were similar in intact and VX rats, but resistance index differed between all groups (0.70 [+ or -] 0.02 vs. 0.78 [+ or -] 0.02 vs. 0.85 [+ or -] 0.02; P < 0.05, intact vs. VX vs. DNX), indicating differential reactivity of renal vasculature. [[??]O.sub.2] 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. renal nerve; oxygen delivery

The idea that an osmotically inactive [Na.sup.+] storage pool exists that can be varied to accommodate states of [Na.sup.+] retention and/or [Na.sup.+] 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.sup.+] 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 [Na.sup.+], [K.sup.+], and water content. Three weeks of growth reduced the total body [Na.sup.+] content relative to dry weight (rTB[Na.sup.+]) by 23%. This 'growth-programmed' [Na.sup.+] loss originated from the bone and the completely skinned and bone-removed carcasses. The [Na.sup.+] loss was osmotically inactive (45-50%) or osmotically active (50-55%). In rats aged 10 wk, compared with HS, 4 wk of LS reduced rTB[Na.sup.+] by 9%. This dietary-induced [Na.sup.+] loss was osmotically inactive ([approximately equal to] 50%) and originated largely from the skin, while [approximately equal to] 50% was osmotically active. LS for 1 wk did not reduce skin [Na.sup.+] content. The mobilization of osmotically inactive skin [Na.sup.+] with long-term salt deprivation was associated with decreased negatively charged skin glycosaminoglycan content and thereby a decreased water-free [Na.sup.+] 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. extrarenal sodium balance; hypertension; volume; sodium reservoirs; glycosaminoglycans doi:10.1152/ajprenal.00300.2006

Induction of streptozotocin (STZ) diabetes in hypertensive rats transgenic for the mouse ren-2 gene (TGR) 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 II type 1 receptor blocker losartan (1 mg*[kg.sup.-1]*[day.sup.-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 TGR 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. angiotensin; nephrosclerosis; macrophages; glomerulosclerosis

The microfibrillar protein fibrillin-1 is a component of the mesangial matrix. Detects 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 due to a compensatory upregulation of decorin. We conclude that fibrillin-1 may contribute to glomerular damage in hypertensive and diabetic kidney disease. deoxycorticosterone acetate hypertension; fibrillin-1-underexpressing mice; glomerular damage: streptozotocin; diabetes

The idea that [Na.sup.+] retention inevitably leads to water retention is compelling; however, were [Na.sup.+] accumulation in part osmotically inactive, regulatory alternatives would be available. We speculated that in DOCA-salt rats [Na.sup.+] 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.sup.+], [K.sup.+], and water were measured in skin, bone, muscle, and total body by desiccation and consecutive dry ashing. DOCA-salt led to total body [Na.sup.+] excess (0.255 [+ or -] 0.022 vs. 0.170 [+ or -] 0.010 mmol/g dry wt; P < 0.001), whereas water retention was only moderate (0.685 [+ or -] 0.119 vs. 0.648 [+ or -] 0.130 ml/g wet wt; P < 0.001). Muscle [Na.sup.+] retention (0.220 [+ or -] 0.029 vs. 0.145 [+ or -] 0.021 mmol/g dry wt; P < 0.01) in DOCA-salt was compensated by muscle [K.sup.+] loss, indicating osmotically neutral [Na.sup.+]/[K.sup.+] exchange. Skin [Na.sup.+] retention (0.267 [+ or -] 0.049 vs. 0.152 [+ or -] 0.014 mmol/g dry wt; P < 0.001) in DOCA-salt rats was not balanced by [K.sup.+] loss, indicating osmotically inactive skin [Na.sup.+] storage. We conclude that DOCA-salt leads to tissue [Na.sup.+] excess relative to water. The relative [Na.sup.+] excess is achieved by two distinct mechanisms, namely, osmotically inactive [Na.sup.+] storage and osmotically neutral [Na.sup.+] retention balanced by [K.sup.+] loss. This 'internal [Na.sup.+] escape' allows the maintenance of volume homeostasis despite increased total body [Na.sup.+]. hypertension; sodium storage; hypertensive rats; mineralocorticoid escape

We tested the hypothesis that angiotensin II is likely to he 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 min) to decrease renal sympathetic nerve activity. Untreated animals, rats with renal denervation or pretreated with a nonhypotensive dose of an angiotensin II type 1 receptor antagonist were studied. The renal renin-angiotensin system was assessed by immunohistochemistry and RT-PCR. Rats with BDL excreted only 71 [+ or -] 4% of the administered volume load. In cirrhotic rats pretreated with an angiotensin II [AT.sub.1] 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 I1 and renin. We speculate that similar changes may contribute to long-term volume retention in liver cirrhosis. liver cirrhosis; nitric oxide; excretion

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 ([+ or -] 4, [+ or -] 6, [+ or -] 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 [+ or -] 3 Hz (approximately +602%); aortic occlusion: +15 [+ or -] 3 Hz (approximately +553%); 70 units; P < 0.05]. VExp and hHem (n = 6) increased CNFA [VExp: +10 [+ or -] 4 Hz (approximately +1,033%); hHem: +10 [+ or -] 2 Hz (approximately +1,225%); P < 0.05]. An increase in CPP increased CNFA [+2 [+ or -] 1 Hz (approximately +225%); P < 0.05], whereas a decrease in CPP decreased CNFA [-0.8 [+ or -] 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. cardiac afferent C fiber; renal sympathetic nerve activity; cardiorenal reflexes