scholarly journals Renal Cortical Vasoconstriction Contributes to Development of Salt-Sensitive Hypertension after Angiotensin II Exposure

2001 ◽  
Vol 12 (11) ◽  
pp. 2263-2271
Author(s):  
MARTHA FRANCO ◽  
EDILIA TAPIA ◽  
JOSÉ SANTAMARÍA ◽  
IGNACIO ZAFRA ◽  
ROMEO GARCÍA-TORRES ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Plasma Flow ◽  
Critical Role ◽  
Progressive Increase ◽  
Tubulointerstitial Injury ◽  
High Salt Diet ◽  
Single Nephron ◽  
Glomerular Hemodynamics ◽  
Salt Sensitive Hypertension

Abstract. Rats that are administered angiotensin II (AngII) for 2 wk develop persistent salt-sensitive hypertension, which can be prevented by the immunosuppressor mycophenolate mofetil (MMF) given during the AngII infusion. This study examined the contribution of glomerular hemodynamics (GFR dynamics) in the post-AngII hypertensive response to a high-salt diet (HSD) and the effect of MMF treatment. During AngII administration, rats developed severe hypertension (systolic BP [SBP], 185 ± 3.9 mmHg), proteinuria, afferent and efferent vasoconstriction, and glomerular hypertension. Rats that received AngII+MMF showed similar responses to AngII; however, they developed lower proteinuria (P < 0.05). At 2 wk, AngII was withdrawn and SBP returned toward normal. Rats were then placed on an HSD (4% NaCl), resulting in a progressive increase in SBP (155 ± 8.2 mmHg at week 1 and 163 ± 4.5 mmHg at week 5). GFR dynamic alterations persisted after AngII was stopped, i.e., afferent and efferent vasoconstriction, decreased glomerular plasma flow and single-nephron GFR, and lower ultrafiltration coefficient. These changes correlated with the thickening of the afferent arteriole and with focal tubulointerstitial injury. In the AngII+MMF group, SBP remained unchanged throughout the HSD period (146 ± 2.3 mmHg at week 1 and 148 ± 4.4 mmHg at week 5) in association with less afferent arteriolar thickening and tubulointerstitial injury. Single-nephron GFR, glomerular plasma flow, efferent resistance, and ultrafiltration coefficient returned to normal with a significant reduction in afferent resistance. These results suggest a critical role of cortical vasoconstriction in salt-sensitive hypertension. The MMF-induced prevention of these changes suggests that immune mechanisms are involved in the vasoconstrictive response.

Role of angiotensin II in experimental membranous nephropathy

1988 ◽  
Vol 254 (4) ◽  
pp. F500-F506
Author(s):  
F. B. Gabbai ◽  
C. B. Wilson ◽  
R. C. Blantz
Keyword(s):  
Angiotensin Ii ◽  
Hydrostatic Pressure ◽  
Membranous Nephropathy ◽  
Enzyme Inhibitor ◽  
Chronic Administration ◽  
Ang Ii ◽  
Glomerular Injury ◽  
Single Nephron ◽  
Glomerular Hemodynamics

Glomerular hemodynamics measurements in rats with experimental membranous nephropathy [passive Heymann nephritis (PHN)] have demonstrated that the appearance of proteinuria 5 days after administration of anti-Fx1A antibody is temporally related to changes in the glomerular ultrafiltration coefficient (LpA). Previous studies in other models of glomerular injury have suggested a significant role for angiotensin II (ANG II) in the glomerular hemodynamic abnormalities. To evaluate the possible role of ANG II in the LpA decrease, converting enzyme inhibitor (CEI) was administered acutely or chronically (5 days before and after induction of PHN) to rats with PHN. Acute ANG II blockade produced a fall in mean arterial pressure (MAP), single-nephron glomerular filtration rate (SNGFR), absolute proximal reabsorption (APR), single-nephron plasma flow, single-nephron blood flow, and glomerular capillary hydrostatic pressure (PG); however, no changes in LpA were detected. Chronic administration of CEI (MK421, 5 mg.kg-1.day-1) in the drinking water was associated with a fall in MAP; however, both SNGFR and APR increased. PG and the transcapillary hydrostatic pressure gradient were unchanged, and LpA remained depressed. These results suggest that reduction of LpA in rats with PHN is ANG II independent and that other mechanisms are required to explain these changes in glomerular hemodynamics.

Regulatory role of prostanoids in glomerular microcirculation of remnant nephrons

1987 ◽  
Vol 252 (5) ◽  
pp. F829-F837 ◽  
Author(s):  
K. A. Nath ◽  
D. H. Chmielewski ◽  
T. H. Hostetter
Keyword(s):  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Plasma Flow ◽  
Filtration Rate ◽  
Prostaglandin E ◽  
Acute Administration ◽  
Sprague Dawley ◽  
Single Nephron ◽  
Glomerular Hemodynamics

The glomerular microcirculation of the remnant nephron is characterized by reduced afferent (RA) and efferent (RE) arteriolar resistances and markedly increased single nephron glomerular plasma flow and filtration rates. We investigated the role of prostanoid production in mediating these adaptive alterations in glomerular hemodynamics after the reduction of renal mass. Acute administration of indomethacin, 5 mg/kg iv in anesthetized euvolemic, Sprague-Dawley rats with intact kidneys led to no significant alteration in renal hemodynamics, whereas in similarly prepared subtotally nephrectomized rats such inhibition significantly reduced remnant kidney glomerular filtration rate from 0.57 +/- 0.07 to 0.45 +/- 0.05 ml/min and single nephron glomerular filtration rate (SNGFR) from 93 +/- 4 to 72 +/- 5 nl/min. This reduction in SNGFR was due to diminutions in the glomerular ultrafiltration coefficient (Kf) from basal values of 0.061 +/- 0.004 to 0.050 +/- 0.004 nl X s-1 X mmHg-1 and in initial glomerular capillary plasma flow rate (QA) from 416 +/- 42 to 321 +/- 42 nl/min. The decrease in QA was a consequence of proportional increases in RA and RE. In other groups of animals we demonstrated that urinary excretions of both vasodilatory as well as vasoconstrictor prostanoids per surviving nephron increase several fold in subtotally nephrectomized rats compared with rats with intact kidneys and that administration of indomethacin, 5 mg/kg iv, reduced urinary excretions of both vasodilatory prostaglandins, prostaglandin E and 6-keto-prostaglandin F1 alpha, as well as vasoconstrictor prostanoid, thromboxane B2, to the same degrees in both subtotally nephrectomized rats and rats with intact kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Metabolic Syndrome and Salt-Sensitive Hypertension in Polygenic Obese TALLYHO/JngJ Mice: Role of Na/K-ATPase Signaling

2019 ◽  
Vol 20 (14) ◽  
pp. 3495 ◽  
Author(s):  
Yanling Yan ◽  
Jiayan Wang ◽  
Muhammad A. Chaudhry ◽  
Ying Nie ◽  
Shuyan Sun ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Significant Rise ◽  
Protein Carbonylation ◽  
High Salt ◽  
Kidney Cortex ◽  
High Salt Diet ◽  
Salt Diet ◽  
Salt Sensitive Hypertension

We have demonstrated that Na/K-ATPase acts as a receptor for reactive oxygen species (ROS), regulating renal Na+ handling and blood pressure. TALLYHO/JngJ (TH) mice are believed to mimic the state of obesity in humans with a polygenic background of type 2 diabetes. This present work is to investigate the role of Na/K-ATPase signaling in TH mice, focusing on susceptibility to hypertension due to chronic excess salt ingestion. Age-matched male TH and the control C57BL/6J (B6) mice were fed either normal diet or high salt diet (HS: 2, 4, and 8% NaCl) to construct the renal function curve. Na/K-ATPase signaling including c-Src and ERK1/2 phosphorylation, as well as protein carbonylation (a commonly used marker for enhanced ROS production), were assessed in the kidney cortex tissues by Western blot. Urinary and plasma Na+ levels were measured by flame photometry. When compared to B6 mice, TH mice developed salt-sensitive hypertension and responded to a high salt diet with a significant rise in systolic blood pressure indicative of a blunted pressure-natriuresis relationship. These findings were evidenced by a decrease in total and fractional Na+ excretion and a right-shifted renal function curve with a reduced slope. This salt-sensitive hypertension correlated with changes in the Na/K-ATPase signaling. Specifically, Na/K-ATPase signaling was not able to be stimulated by HS due to the activated baseline protein carbonylation, phosphorylation of c-Src and ERK1/2. These findings support the emerging view that Na/K-ATPase signaling contributes to metabolic disease and suggest that malfunction of the Na/K-ATPase signaling may promote the development of salt-sensitive hypertension in obesity. The increased basal level of renal Na/K-ATPase-dependent redox signaling may be responsible for the development of salt-sensitive hypertension in polygenic obese TH mice.

scholarly journals Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2

2008 ◽  
Vol 295 (2) ◽  
pp. F462-F470 ◽  
Author(s):  
Peijun P. Shi ◽  
Xiao R. Cao ◽  
Eileen M. Sweezer ◽  
Thomas S. Kinney ◽  
Nathan R. Williams ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Critical Role ◽  
Specific Inhibitor ◽  
Normal Diet ◽  
High Salt ◽  
High Salt Diet ◽  
Salt Diet ◽  
Ww Domains ◽  
Salt Sensitive Hypertension

Nedd4-2 has been proposed to play a critical role in regulating epithelial Na+ channel (ENaC) activity. Biochemical and overexpression experiments suggest that Nedd4-2 binds to the PY motifs of ENaC subunits via its WW domains, ubiquitinates them, and decreases their expression on the apical membrane. Phosphorylation of Nedd4-2 (for example by Sgk1) may regulate its binding to ENaC, and thus ENaC ubiquitination. These results suggest that the interaction between Nedd4-2 and ENaC may play a crucial role in Na+ homeostasis and blood pressure (BP) regulation. To test these predictions in vivo, we generated Nedd4-2 null mice. The knockout mice had higher BP on a normal diet and a further increase in BP when on a high-salt diet. The hypertension was probably mediated by ENaC overactivity because 1) Nedd4-2 null mice had higher expression levels of all three ENaC subunits in kidney, but not of other Na+ transporters; 2) the downregulation of ENaC function in colon was impaired; and 3) NaCl-sensitive hypertension was substantially reduced in the presence of amiloride, a specific inhibitor of ENaC. Nedd4-2 null mice on a chronic high-salt diet showed cardiac hypertrophy and markedly depressed cardiac function. Overall, our results demonstrate that in vivo Nedd4-2 is a critical regulator of ENaC activity and BP. The absence of this gene is sufficient to produce salt-sensitive hypertension. This model provides an opportunity to further investigate mechanisms and consequences of this common disorder.

Polymorphisms of EDNRB, ATG, and ACE genes in salt-sensitive hypertensionThis article is one of a selection of papers published in the special issue (part 2 of 2) on Forefronts in Endothelin.

2008 ◽  
Vol 86 (8) ◽  
pp. 505-510 ◽  
Author(s):  
Jessica Caprioli ◽  
Caterina Mele ◽  
Chiara Mossali ◽  
Laura Gallizioli ◽  
Gilberta Giacchetti ◽  
...  
Keyword(s):  
Protective Role ◽  
Receptor Subtype ◽  
Genotype Distribution ◽  
High Salt Diet ◽  
Subtype B ◽  
Salt Depletion ◽  
Sensitivity Data ◽  
Pressure Changes ◽  
Salt Sensitive Hypertension

Almost 50% of hypertensive individuals manifest blood pressure changes in response to salt depletion or repletion and are termed “salt sensitive” (SS). Blunted activity of the endothelin (ET) system and the renin–angiotensin–aldosterone system (RAAS) have been reported as possible mechanisms contributing to salt sensitivity. Data are available that endothelin receptor subtype B (ETBR)-deficient rats develop salt-sensitive hypertension when fed a high-salt diet. Whether the ETBR gene (EDNRB) is involved in genetic predisposition to human salt-sensitive hypertension has not been studied so far. We screened EDNRB in 104 hypertensive patients (49 salt sensitive and 55 salt resistant) and 110 normotensive controls. No new sequence variation was found, but genotype distribution of the common polymorphism G1065A revealed that the AA + GA genotypes were significantly more frequent in salt-resistant than in salt-sensitive individuals (p = 0.007), suggesting a protective role for the A allele. We also screened angiotensinogen gene AGT M235T and angiotensin-converting enzyme insertion/deletion polymorphism ACE I/D and found an association between TT genotype and hypertension. A possible synergistic effect to salt-sensitive hypertension was found by combining EDNRB GG with ACE DD/ID genotypes. In conclusion, our data confirm the role of ET system and RAAS in salt-sensitive hypertension.

Role of angiotensin II in tubulointerstitial injury

2001 ◽  
Vol 21 (6) ◽  
pp. 554-562 ◽  
Author(s):  
Zemin Cao ◽  
Mark E. Cooper
Keyword(s):  
Angiotensin Ii ◽  
Tubulointerstitial Injury

Post-cyclosporine-mediated hypertension and nephropathy: amelioration by vascular endothelial growth factor

2001 ◽  
Vol 280 (4) ◽  
pp. F727-F736 ◽  
Author(s):  
Duk-Hee Kang ◽  
Yoon-Goo Kim ◽  
Takeshi F. Andoh ◽  
Katherine L. Gordon ◽  
Shin-Ichi Suga ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
High Salt ◽  
Vascular Endothelial ◽  
Tubulointerstitial Injury ◽  
Angiogenic Growth Factors ◽  
High Salt Diet ◽  
Salt Diet ◽  
Salt Sensitive Hypertension ◽  
Endothelial Growth Factor

Recent studies have demonstrated a role for microvascular and tubulointerstitial injury in some models of salt-sensitive hypertension. We utilized a model of post-cyclosporin A (CsA) nephropathy and hypertension to test the hypothesis that treatment with an angiogenic factor aimed at ameliorating the microvascular and renal injury would prevent the development of hypertension. CsA was administered with a low-salt diet for 45 days, resulting in a renal lesion characterized by afferent arteriolopathy, focal peritubular capillary loss, and tubulointerstitial fibrosis. Rats were then placed on a high-salt diet and randomized to receive either vascular endothelial growth factor (VEGF121) or vehicle for 14 days. Placement of rats with established CsA nephropathy on a high-salt diet results in the rapid development of salt-sensitive hypertension. VEGF121 treatment resulted in lower blood pressure, and this persisted on discontinuing the VEGF. VEGF121 treatment was also associated with a decrease in osteopontin expression, macrophage infiltration, and collagen III deposition and markedly stimulated resolution of the arteriolopathy (20.9 ± 7.8 vs. 36.9 ± 6.1%, VEGF vs. vehicle, P < 0.05). In conclusion, CsA-associated renal microvascular and tubulointerstitial injury results in the development of salt-sensitive hypertension. Treatment of animals with established CsA nephropathy with VEGF reduces the hypertensive response and accelerates histological recovery. The vascular protective effect of VEGF may be due to the improvement of arteriolopathy. Angiogenic growth factors may represent a novel strategy for treating CsA-associated hypertension and renal disease.

Role of deep nephrons and the terminal collecting duct in a mannitol-induced diuresis

1981 ◽  
Vol 240 (5) ◽  
pp. F411-F422 ◽  
Author(s):  
J. Buerkert ◽  
D. Martin ◽  
J. Prasad ◽  
D. Trigg
Keyword(s):  
Plasma Flow ◽  
Collecting Duct ◽  
Renal Plasma Flow ◽  
Distal Tubule ◽  
Sodium Reabsorption ◽  
Water Reabsorption ◽  
Single Nephron ◽  
Papillary Collecting Duct ◽  
Reduced Water

Recollection micropuncture in Munich-Wistar rats was used to study the effects of intravenous hypertonic mannitol infusions on fluid reabsorption by surface nephrons, prior to the bend of Henle's loop of deep nephrons, and along the papillary collecting duct. During mannitol diuresis, single nephron glomerular filtration rate rose significantly in surface nephrons but fell in deep nephrons. Although mannitol increased the delivery of sodium and water to the end of the proximal tubule and to the first portion of the distal tubule of surface nephrons, water and sodium were reabsorbed between these two sites. In deep nephrons, water reabsorption prior to the bend of the loop of Henle was significantly decreased. Absolute sodium delivery to this site was reduced despite a marked decrease in fractional sodium reabsorption prior to the bend. Papillary osmolality was decreased. Renal plasma flow and inner medullary plasma flow (IMPF) increased proportionally. The reduced water extraction prior to the bend of deep nephrons and the decrease in papillary osmolality could have been partly due to a concomitant increase in IMPF and a decrease in sodium delivery to the medulla. The reabsorption of delivered sodium and water by the papillary collecting duct was reduced to a greater extent than could be expected from the increase in sodium delivery.

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