Renal endosomes contain angiotensin peptides, converting enzyme, and AT1A receptors

1999 ◽  
Vol 277 (2) ◽  
pp. F303-F311 ◽  
Author(s):  
John D. Imig ◽  
Gabriel L. Navar ◽  
Li-Xian Zou ◽  
Katie C. O’Reilly ◽  
Patricia L. Allen ◽  
...  
Keyword(s):  
High Salt ◽  
Dietary Sodium ◽  
Kidney Cortex ◽  
Ang Ii ◽  
Converting Enzyme ◽  
High Salt Diet ◽  
Salt Diet ◽  
Angiotensin Peptides ◽  
Low Salt ◽  
Ace Activity

Kidney cortex and proximal tubular angiotensin II (ANG II) levels are greater than can be explained on the basis of circulating ANG II, suggesting intrarenal compartmentalization of these peptides. One possible site of intracellular accumulation is the endosomes. In the present study, we tested for endosomal ANG I, ANG II, angiotensin type 1A receptor (AT1A), and angiotensin converting enzyme (ACE) activity and determined whether these levels are regulated by salt intake. Male Sprague-Dawley rats were fed chow containing either high or low dietary sodium for 10–14 days. Blood and kidneys were harvested and processed for measurement of plasma, kidney, and renal intermicrovillar cleft and endosomal angiotensin levels. Kidney ANG I averaged 179 ± 20 fmol/g and ANG II averaged 258 ± 36 fmol/g in rats fed a high-sodium diet and were significantly higher, averaging 347 ± 58 fmol/g and 386 ± 55 fmol/g, respectively, in rats fed a low-salt diet. Renal intermicrovillar clefts and endosomes contained ANG I and ANG II. Intermicrovillar cleft ANG I and ANG II levels averaged 8.4 ± 2.6 and 74 ± 26 fmol/mg, respectively, in rats fed a high-salt diet and 7.6 ± 1.7 and 70 ± 25 fmol/mg in rats fed a low-salt diet. Endosomal ANG I and ANG II levels averaged 12.3 ± 4.4 and 43 ± 19 fmol/mg, respectively, in rats fed a high-salt diet, and these levels were similar to those observed in rats fed a low-salt diet. Renal endosomes from rats fed a low-salt diet demonstrated significantly more AT1A receptor binding compared with rats fed a high-salt diet. ACE activity was detectable in renal intermicrovillar clefts and was 2.5-fold higher than the levels observed in renal endosomes. Acute enalaprilat treatment decreased ACE activity in renal intermicrovillar clefts by 90% and in renal endosomes by 84%. Likewise, intermicrovillar cleft and endosomal ANG II levels decreased by 61% and 52%, respectively, in enalaprilat-treated animals. These data demonstrate the presence of intact angiotensin peptides and ACE activity in renal intermicrovillar clefts and endosomes, indicating that intact angiotensin peptides are formed and/or trafficked through intracellular endosomal compartments and are dependent on ACE activity.

Upregulation of macula densa cyclooxygenase-2 expression is not dependent on glomerular filtration

2004 ◽  
Vol 287 (1) ◽  
pp. F95-F101 ◽  
Author(s):  
Frank Schweda ◽  
Martin Kammerl ◽  
Charlotte Wagner ◽  
Bernhard K. Krämer ◽  
Armin Kurtz
Keyword(s):  
Mrna Expression ◽  
Glomerular Filtration ◽  
High Salt ◽  
Kidney Cortex ◽  
High Salt Diet ◽  
Salt Diet ◽  
Contralateral Kidney ◽  
Low Salt ◽  
Renin Mrna ◽  
Cox 2

Although the regulation of cyclooxygenase-2 (COX-2) expression in the kidney cortex has been extensively characterized, the physiological control mechanisms of COX-2 expression at the level of the kidney and at the level of the tubular cells are not well understood. Based on the current hypothesis that tubular salt transport might be a crucial regulator of COX-2 expression, this study aimed to determine the impact of salt delivery to the tubules (glomerular filtration) for the regulation of COX-2 in the kidney cortex in vivo. To this end, glomerular filtration of the right kidney was abrogated by the ligation of the right ureter of male Sprague-Dawley rats. After 1 wk of ligation, the animals were treated with subcutaneous infusions of furosemide (12 mg·kg−1·day−1) or with a low-salt or a high-salt diet (0.02% wt/wt; 8% wt/wt), and COX-2 as well as renin mRNA expression were determined in the ligated and the nonligated contralateral kidney. During ureteral ligation, hydronephrosis developed with a reduction of medullary mass, while the cortex was preserved. Expressions of the Na-K-2Cl cotransporter isoforms A and B were both reduced in the hydronephrotic cortex to 70 and 35% of the corresponding contralateral intact kidney. Despite the abrogation of glomerular filtration, detected by inulin clearance measurements, renocortical COX-2 mRNA abundance was stimulated by furosemide treatment (3.2-fold) or low-salt diet (2.9-fold) to similar degrees compared with the intact contralateral kidney (2.7-fold for both treatments), whereas a high-salt diet did not significantly suppress COX-2 mRNA in the macula densa region of either kidney. Renin mRNA expression was regulated strictly in parallel in both kidneys, a low-salt diet or furosemide treatment stimulating and a high-salt diet suppressing it. We conclude from these findings that salt delivery to the tubules is not an essential requirement for the upregulation of COX-2 by salt deficiency or by loop diuretics in the rat kidney cortex nor is it for chronic stimulation of renin mRNA expression.

Contribution of cytochrome P-450 ω-hydroxylase to altered arteriolar reactivity with high-salt diet and hypertension

2000 ◽  
Vol 278 (5) ◽  
pp. H1517-H1526 ◽  
Author(s):  
Jefferson C. Frisbee ◽  
John R. Falck ◽  
Julian H. Lombard
Keyword(s):  
Renal Mass ◽  
High Salt ◽  
Ang Ii ◽  
Cremaster Muscle ◽  
High Salt Diet ◽  
Salt Diet ◽  
Low Salt ◽  
Resting Tone ◽  
Cytochrome P 450 ◽  
Arteriolar Diameter

The present study evaluated the contribution of cytochrome P-450 ω-hydroxylase in modulating the reactivity of cremaster muscle arterioles in normotensive rats on high-salt (HS) and low-salt (LS) diet and in rats with reduced renal mass hypertension (RRM-HT). Changes in arteriolar diameter in response to ACh, sodium nitroprusside (SNP), ANG II, and elevated O2 were measured via television microscopy under control conditions and following cytochrome P-450 ω-hydroxylase inhibition with 17-octadecynoic acid (17-ODYA) or N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS). In normotensive rats on either LS or HS diet, resting tone was unaffected and arteriolar reactivity to ACh or SNP was minimally affected by cytochrome P-450 ω-hydroxylase inhibition. In RRM-HT rats, cytochrome P-450 ω-hydroxylase inhibition reduced resting tone and significantly enhanced arteriolar dilation to ACh and SNP. Treatment with 17-ODYA or DDMS inhibited arteriolar constriction to ANG II and O2 in all the groups, although the degree of inhibition was greater in RRM-HT than in normotensive animals. These results suggest that metabolites of cytochrome P-450 ω-hydroxylase contribute to the altered reactivity of skeletal muscle arterioles to vasoconstrictor and vasodilator stimuli in RRM-HT.

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.

Renal endothelin in chronic angiotensin II hypertension

2002 ◽  
Vol 283 (1) ◽  
pp. R243-R248 ◽  
Author(s):  
Jennifer M. Sasser ◽  
Jennifer S. Pollock ◽  
David M. Pollock
Keyword(s):  
Sodium Intake ◽  
Renal Tissue ◽  
High Salt ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Outer Medulla ◽  
High Salt Diet ◽  
Salt Diet ◽  
Sprague Dawley Rats ◽  
Saline Vehicle

To determine the influence of chronic ANG II infusion on urinary, plasma, and renal tissue levels of immunoreactive endothelin (ET), ANG II (65 ng/min) or saline vehicle was delivered via osmotic minipump in male Sprague-Dawley rats given either a high-salt diet (10% NaCl) or normal-salt diet (0.8% NaCl). High-salt diet alone caused a slight but not statistically significant increase (7 ± 1%) in mean arterial pressure (MAP). MAP was significantly increased in ANG II-infused rats (41 ± 10%), and the increase in MAP was significantly greater in ANG II rats given a high-salt diet (59 ± 1%) compared with the increase observed in rats given a high-salt diet alone or ANG II infusion and normal-salt diet. After a 2-wk treatment, urinary excretion of immunoreactive ET was significantly increased by ∼50% in ANG II-infused animals and by over 250% in rats on high-salt diet, with or without ANG II infusion. ANG II infusion combined with high-salt diet significantly increased immunoreactive ET content in the cortex and outer medulla, but this effect was not observed in other groups. In contrast, high-salt diet, with or without ANG II infusion, significantly decreased immunoreactive ET content within the inner medulla. These data indicate that chronic elevations in ANG II levels and sodium intake differentially affect ET levels within the kidney and provide further support for the hypothesis that the hypertensive effects of ANG II may be due to interaction with the renal ET system.

scholarly journals Proximal tubule-targeted overexpression of the Cyp4a12-20-HETE synthase promotes salt-sensitive hypertension in male mice

2020 ◽  
Vol 319 (1) ◽  
pp. R87-R95
Author(s):  
Ankit Gilani ◽  
Kevin Agostinucci ◽  
Jonathan V. Pascale ◽  
Sakib Hossain ◽  
Sharath Kandhi ◽  
...  
Keyword(s):  
Proximal Tubule ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Fold Increase ◽  
High Salt ◽  
Kidney Cortex ◽  
Male Mice ◽  
High Salt Diet ◽  
Salt Diet ◽  
Renal Microvasculature ◽  
Salt Sensitive Hypertension

20-Hydroxyeicosatetraenoic acid (20-HETE) has been linked to blood pressure (BP) regulation via actions on the renal microvasculature and tubules. We assessed the tubular 20-HETE contribution to hypertension by generating transgenic mice overexpressing the CYP4A12-20-HETE synthase (PT-4a12 mice) under the control of the proximal tubule (PT)-specific promoter phosphoenolpyruvate carboxykinase (PEPCK). 20-HETE levels in the kidney cortex of male (967 ± 210 vs. 249 ± 69 pg/mg protein) but not female (121 ± 15 vs. 92 ± 11 pg/mg protein) PT-4a12 mice showed a 2.5-fold increase compared with wild type (WT). Renal cortical Cyp4a12 mRNA and CYP4A12 protein in male but not female PT-4a12 mice increased by two- to threefold compared with WT. Male PT-4a12 mice displayed elevated BP (142 ± 1 vs. 111 ± 4 mmHg, P < 0.0001), whereas BP in female PT-4a12 mice was not significantly different from WT (118 ± 2 vs. 117 ± 2 mmHg; P = 0.98). In male PT-4a12 mice, BP decreased when mice were transitioned from a control-salt (0.4%) to a low-salt diet (0.075%) from 135 ± 4 to 120 ± 6 mmHg ( P < 0.01) and increased to 153 ± 5 mmHg ( P < 0.05) when mice were placed on a high-salt diet (4%). Female PT-4a12 mice did not show changes in BP on either low- or high-salt diet. In conclusion, the expression of Cyp4a12 driven by the PEPCK promoter is sex specific, probably because of its X-linkage. The salt-sensitive hypertension seen in PT-4a12 male mice suggests a potential antinatriuretic activity of 20-HETE that needs to be further explored.

scholarly journals AT1 receptor participates in the cardiac hypertrophy induced by resistance training in rats

2008 ◽  
Vol 295 (2) ◽  
pp. R381-R387 ◽  
Author(s):  
Valerio G. Barauna ◽  
Flávio C. Magalhaes ◽  
Jose E. Krieger ◽  
Edilamar M. Oliveira
Keyword(s):  
Resistance Training ◽  
Left Ventricle ◽  
Cardiac Hypertrophy ◽  
Receptor Gene ◽  
Weight Ratio ◽  
High Salt ◽  
Receptor Expression ◽  
Ang Ii ◽  
High Salt Diet ◽  
Salt Diet

Resistance training is accompanied by cardiac hypertrophy, but the role of the renin-angiotensin system (RAS) in this response is elusive. We evaluated this question in 36 male Wistar rats divided into six groups: control ( n = 6); trained ( n = 6); control + losartan (10 mg·kg−1·day−1, n = 6); trained + losartan ( n = 6); control + high-salt diet (1%, n = 6); and trained + high-salt diet (1%, n = 6). High salt was used to inhibit the systemic RAS and losartan to block the AT1 receptor. The exercise protocol consisted of: 4 × 12 bouts, 5×/wk during 8 wk, with 65–75% of one repetition maximum. Left ventricle weight-to-body weight ratio increased only in trained and trained + high-salt diet groups (8.5% and 10.6%, P < 0.05) compared with control. Also, none of the pathological cardiac hypertrophy markers, atrial natriuretic peptide, and αMHC (α-myosin heavy chain)-to-βMHC ratio, were changed. ACE activity was analyzed by fluorometric assay (systemic and cardiac) and plasma renin activity (PRA) by RIA and remained unchanged upon resistance training, whereas PRA decreased significantly with the high-salt diet. Interestingly, using Western blot analysis and RT-PRC, no changes were observed in cardiac AT2 receptor levels, whereas the AT1 receptor gene (56%, P < 0.05) and protein (31%, P < 0.05) expressions were upregulated in the trained group. Also, cardiac ANG II concentration evaluated by ELISA remained unchanged (23.27 ± 2.4 vs. 22.01 ± 0.8 pg/mg, P > 0.05). Administration of a subhypotensive dose of losartan prevented left ventricle hypertrophy in response to the resistance training. Altogether, we provide evidence that resistance training-induced cardiac hypertrophy is accompanied by induction of AT1 receptor expression with no changes in cardiac ANG II, which suggests a local activation of the RAS consistent with the hypertrophic response.

scholarly journals Eplerenone inhibits aldosterone-induced renal expression of cyclooxygenase

2012 ◽  
Vol 13 (3) ◽  
pp. 353-359 ◽  
Author(s):  
MA Bayorh ◽  
A Rollins-Hairston ◽  
J Adiyiah ◽  
D Lyn ◽  
D Eatman
Keyword(s):  
Salt Intake ◽  
High Salt ◽  
Prostaglandin E ◽  
Renal Tubules ◽  
Protective Effects ◽  
High Salt Diet ◽  
Salt Diet ◽  
High Salt Intake ◽  
Low Salt ◽  
Cox 2

Introduction: The upregulation of cyclooxygenase (COX) expression by aldosterone (ALDO) or high salt diet intake is very interesting and complex in the light of what is known about the role of COX in renal function. Thus, in this study, we hypothesize that apocynin (APC) and/or eplerenone (EPL) inhibit ALDO/salt-induced kidney damage by preventing the production of prostaglandin E2 (PGE2). Methods: Dahl salt-sensitive rats on either a low-salt or high-salt diet were treated with ALDO (0.2 mg pellet) in the presence of EPL (100 mg/kg/day) or APC (1.5 mM). Indirect blood pressure, prostaglandins and ALDO levels and histological changes were measured. Results: Cyclooxygenase-2 (COX-2) levels were upregulated in the renal tubules and peritubular vessels after high-salt intake, and APC attenuated renal tubular COX-2 protein expression induced by ALDO. Plasma PGE2 levels were significantly reduced by ALDO in the rats fed a low-salt diet when compared to rats fed a high-salt diet. PGE2 was blocked by EPL but increased in the presence of APC. Conclusions: The beneficial effects of EPL may be associated with an inhibition of PGE2. The mechanism underlying the protective effects of EPL is clearly distinct from that of APC and suggests that these agents can have differential roles in cardiovascular disease.

Abstract 376: The Expression of (pro)renin Receptor is Upregulated in the Kidney by High Salt Diet and No Inhibition

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Rong Rong ◽  
Osamu Ito ◽  
Nobuyoshi Mori ◽  
Yuma Tamura ◽  
Akihiro Sakuyama ◽  
...  
Keyword(s):  
Collecting Duct ◽  
High Salt ◽  
Kidney Cortex ◽  
Control Group ◽  
Thick Ascending Limb ◽  
High Salt Diet ◽  
Salt Diet ◽  
Protein Levels ◽  
Nephron Segments ◽  
Sd Rats

The (pro)renin receptor ((P)RR)-bound (pro)renin not only causes the generation of angiotensin II via the increased enzymatic activity, it also activates the receptor’s own intracellular signaling pathways up-regulating the expression of the profibrotic proteins. To clarify the regulation of (P)RR expression, the present study examined the effects of high salt diet and nitric oxide synthase (NOS) inhibition on the (P)RR expression in the kidney. The nephron segments were isolated from male Sprague-Dawley (SD) rats by microdissection and bulk isolation technique, and the (P)RR mRNA and protein expressions were examined by using reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis. In adiition, 5 week-old, male SD rats were randomly divided into 3 groups: a control group, a high salt diet (HS) group and a Nω-Nitro-L-arginine (L-NAME) group, and each group was treated with vehicle, high salt diet (8%, NaCl), or L-NAME (600mg/ml in drinking water), respectively. After 4 weeks, the (P)RR expression in the kidney was compared among these groups. The (P)RR mRNA was expressed in the glomerulus (Glm), the proximal convoluted and straight tubule, the cortical and medullary thick ascending limb (TAL) and collecting duct. The (P)RR protein as well as mRNA was expressed widely in the nephron segments; the preglomerular arteriole, the Glm, the proximal tubules (PT), the medullary TAL (mTAL) and inner medullary collecting duct (IMCD). Compared with the control group, the (P)RR protein levels significantly increased in the kidney cortex of both HS group and L-NAME group by 96% (p<0.01) and 506% (p<0.01) and in the inner medulla of L-NAME group by 148% (p<0.05), but did not significantly change in the outer medulla of HS group or L-NAME group. HS increased the (P)RR protein levels in the Glm and PT by 48% (p<0.05) and 39% (p<0.01), but did not affect them in other nephron segments. These results indicated that (P)RR is expressed widely in the nephron segments and that HS and NOS inhibition upregulate the (P)RR expression in the kidney, suggesting roles of (P)RR in hypertensive kidney disorder.

scholarly journals Discharge of RVLM vasomotor neurons is not increased in anesthetized angiotensin II-salt hypertensive rats

2013 ◽  
Vol 305 (12) ◽  
pp. H1781-H1789 ◽  
Author(s):  
Gustavo R. Pedrino ◽  
Alfredo S. Calderon ◽  
Mary Ann Andrade ◽  
Sergio L. Cravo ◽  
Glenn M. Toney
Keyword(s):  
Sympathetic Nerve Activity ◽  
High Salt ◽  
Ventrolateral Medulla ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Nerve Activity ◽  
High Salt Diet ◽  
Salt Diet ◽  
Salt Hypertension ◽  
Single Unit Recordings

Neurons of the rostral ventrolateral medulla (RVLM) are critical for generating and regulating sympathetic nerve activity (SNA). Systemic administration of ANG II combined with a high-salt diet induces hypertension that is postulated to involve elevated SNA. However, a functional role for RVLM vasomotor neurons in ANG II-salt hypertension has not been established. Here we tested the hypothesis that RVLM vasomotor neurons have exaggerated resting discharge in rats with ANG II-salt hypertension. Rats in the hypertensive (HT) group consumed a high-salt (2% NaCl) diet and received an infusion of ANG II (150 ng·kg−1·min−1 sc) for 14 days. Rats in the normotensive (NT) group consumed a normal salt (0.4% NaCl) diet and were infused with normal saline. Telemetric recordings in conscious rats revealed that mean arterial pressure (MAP) was significantly increased in HT compared with NT rats ( P < 0.001). Under anesthesia (urethane/chloralose), MAP remained elevated in HT compared with NT rats ( P < 0.01). Extracellular single unit recordings in HT ( n = 28) and NT ( n = 22) rats revealed that barosensitive RVLM neurons in both groups (HT, 23 cells; NT, 34 cells) had similar cardiac rhythmicity and resting discharge. However, a greater ( P < 0.01) increase of MAP was needed to silence discharge of neurons in HT (17 cells, 44 ± 5 mmHg) than in NT (28 cells, 29 ± 3 mmHg) rats. Maximum firing rates during arterial baroreceptor unloading were similar across groups. We conclude that heightened resting discharge of sympathoexcitatory RVLM neurons is not required for maintenance of neurogenic ANG II-salt hypertension.

scholarly journals Time course of decompensation after angiotensin II and high-salt diet in Balb/CJ mice suggests pulmonary hypertension-induced cardiorenal syndrome

2019 ◽  
Vol 316 (5) ◽  
pp. R563-R570 ◽  
Author(s):  
Mediha Becirovic-Agic ◽  
Sofia Jönsson ◽  
Maria K. Tveitarås ◽  
Trude Skogstrand ◽  
Tine V. Karlsen ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Angiotensin Ii ◽  
Cardiac Function ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
High Salt ◽  
Ang Ii ◽  
Salt Treatment ◽  
High Salt Diet ◽  
Salt Diet

The genetic background of a mouse strain determines its susceptibility to disease. C57BL/6J and Balb/CJ are two widely used inbred mouse strains that we found react dramatically differently to angiotensin II and high-salt diet (ANG II + Salt). Balb/CJ show increased mortality associated with anuria and edema formation while C57BL/6J develop arterial hypertension but do not decompensate and die. Clinical symptoms of heart failure in Balb/CJ mice gave the hypothesis that ANG II + Salt impairs cardiac function and induces cardiac remodeling in male Balb/CJ but not in male C57BL/6J mice. To test this hypothesis, we measured cardiac function using echocardiography before treatment and every day for 7 days during treatment with ANG II + Salt. Interestingly, pulsed wave Doppler of pulmonary artery flow indicated increased pulmonary vascular resistance and right ventricle systolic pressure in Balb/CJ mice, already 24 h after ANG II + Salt treatment was started. In addition, Balb/CJ mice showed abnormal diastolic filling indicated by reduced early and late filling and increased isovolumic relaxation time. Furthermore, Balb/CJ exhibited lower cardiac output compared with C57BL/6J even though they retained more sodium and water, as assessed using metabolic cages. Left posterior wall thickness increased during ANG II + Salt treatment but did not differ between the strains. In conclusion, ANG II + Salt treatment causes early restriction of pulmonary flow and reduced left ventricular filling and cardiac output in Balb/CJ, which results in fluid retention and peripheral edema. This makes Balb/CJ a potential model to study the adaptive capacity of the heart for identifying new disease mechanisms and drug targets.

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