Abstract P266: Thromboxane-prostanoid Receptors (tp-rs) Mediate Hypertension, H2o2 Generation and Impaired Renal Afferent Arteriolar Myogenic Responses Leading to Nephropathy in Doca/salt Mice

Background: DOCA/uninephrectomy/high salt (DOCA) is a model of hypertensive nephropathy. Afferent arteriolar myogenic responses prevent hypertensive renal barotrauma but myogenic tone is blocked by vascular generation of H 2 O 2 . Since thromboxane-prostanoid receptors (TP-Rs) generate H 2 O 2 , we tested the hypothesis that they mediate hypertensive nephropathy. Methods: DOCA and Sham TP-R +/+ and -/- mice (n=6/group) were studied at 2 weeks and myogenic responses recorded from the diameter of perfused single afferent arterioles studied in a bath preparation during increased perfusion pressure (40 to 80 mmHg). Results: DOCA treatment in TP-R +/+ mice increased (p<0.001) 24-hour excretion of H 2 O 2 (45 ± 3 vs 220 + 15 nmol) , TxB 2 (4 ± 2 vs 29 ± 4 pmol) and albumin (20 ± 5 vs 270 ± 20 mg) and increased MAP by 35 ± 5 mmHg. However, all effects of DOCA were prevented in TP-R -/- mice. Sham treatment had no effect in TPR +/+ or -/- mice. Myogenic responses were severely impaired in DOCA vs sham WT mice (Δ diameter: -4 ± 1 vs -8 ± 1%; p< 0.005). Myogenic responses also were reduced by incubation of arterioles with 10 -10 mol·l -1 of the TP-R mimetic, U-46,619 vs vehicle added to the bath for 10 minutes (Δ diameter: -7 ± 1 vs -10 ± 1%; p<0.01) and in WT mice infused for 3 days with U-46,619 (500 ng·kg -1 ·d -1 x 3) vs vehicle (Δ diameter: -3 ± 1 vs -10 ± 1%; p<0.005). Conclusion: Hypertensive nephropathy is dependent on TP-Rs that mediate the increase in H 2 O 2 and blood pressure and likely the impaired myogenic responses that expose the kidney to barotrauma

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Abstract P435: Differential Responses of Cerebral Cortical and Renal Cortical Microvessels to Perfusion Pressure and Angiotensin II: Effect of Angiotensin II or DOCA/salt Hypertension

Hypertension ◽

10.1161/hyp.70.suppl_1.p435 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Lingli Li ◽

En Yin Lai ◽

William J Welch ◽

Christopher S Wilcox

Keyword(s):

Blood Flow ◽

Angiotensin Ii ◽

Perfusion Pressure ◽

High Salt ◽

Ang Ii ◽

Cerebral Microvessels ◽

Salt Hypertension ◽

Afferent Arterioles ◽

Myogenic Responses ◽

The Brain

Background: The brain and kidney autoregulate their blood flow well yet both suffer from hypertensive damage. We found that a pressor infusion of angiotensin II (Ang II) reduced renal blood flow yet did not change cerebral blood flow. Therefore, we tested the hypothesis that their myogenic and Ang II responses differed. Methods: Cerebral cortical microvessels (cerebral) and renal afferent arterioles (afferent) were isolated and perfused from mice after 4 weeks of hypertension from Ang II infusion /high salt/uninephrectomy (Ang II hypertension) or DOCA/high salt/uninephrectomy (DOCA/salt hypertension) or normotensive controls without Ang II or DOCA (n=4-6 per group). Results: Normal cerebral and afferents had similar myogenic responses (Δ diameter: cerebral -21±3 versus afferent-19±2%, NS), but bath addition of Ang II or norepinephrine contracted afferents strongly (Ang II: -48±5%, P<0.001, NE: -95±2%, P<0.001), yet cerebrals were entirely unresponsive. Myogenic responses in Ang II hypertension were reduced selectively by 40% in cerebral microvessels compared to controls (-13±3 versus -21±3%, P<0.001) yet maintained in afferents (-17±3 versus -19±2%, NS). However, myogenic responses in DOCA/salt hypertension were maintained in both groups. Contractions to Ang II in cerebral microvessels were increased in Ang II hypertension (-5±2 versus 0±1%, P<0.01) and increased in DOCA/salt hypertension (-18±8 versus -2±2%, P<0.01). In contrast, contractions to Ang II in afferent arterioles were reduced 50% in Ang II hypertension (-23±5 versus -48±5%, P<0.001) and reduced 25% in DOCA/salt hypertension (-38±6 versus -50±10%, P=0.05). Conclusions: The kidney is well protected from hypertension and excessive Ang II vasoconstriction. However, the breakdown of myogenic responses in the cerebral microvessels during Ang II hypertension and the enhanced Ang II responses in the cerebral microvessels during Ang II and DOCA/salt hypertension make the brain especially vulnerable to hypertensive ischemia or damage.

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Impaired myogenic constriction of the renal afferent arteriole in a mouse model of reduced βENaC expression

AJP Renal Physiology ◽

10.1152/ajprenal.00638.2011 ◽

2012 ◽

Vol 302 (11) ◽

pp. F1486-F1493 ◽

Cited By ~ 16

Author(s):

Ying Ge ◽

Kimberly Gannon ◽

Monette Gousset ◽

Ruishing Liu ◽

Beau Murphey ◽

...

Keyword(s):

Smooth Muscle ◽

Mouse Model ◽

Vascular Resistance ◽

Perfusion Pressure ◽

Rate Of Change ◽

Renal Vascular Resistance ◽

Myogenic Tone ◽

Afferent Arteriole ◽

Afferent Arterioles ◽

Renal Vascular

Previous studies demonstrate a role for β epithelial Na+ channel (βENaC) protein as a mediator of myogenic constriction in renal interlobar arteries. However, the importance of βENaC as a mediator of myogenic constriction in renal afferent arterioles, the primary site of development of renal vascular resistance, has not been determined. We colocalized βENaC with smooth muscle α-actin in vascular smooth muscle cells in renal arterioles using immunofluorescence. To determine the importance of βENaC in myogenic constriction in renal afferent arterioles, we used a mouse model of reduced βENaC (βENaC m/m) and examined pressure-induced constrictor responses in the isolated afferent arteriole-attached glomerulus preparation. We found that, in response to a step increase in perfusion pressure from 60 to 120 mmHg, the myogenic tone increased from 4.5 ± 3.7 to 27.3 ± 5.2% in +/+ mice. In contrast, myogenic tone failed to increase with the pressure step in m/m mice (3.9 ± 0.8 to 6.9 ± 1.4%). To determine the importance of βENaC in myogenic renal blood flow (RBF) regulation, we examined the rate of change in renal vascular resistance following a step increase in perfusion pressure in volume-expanded animals. We found that, following a step increase in pressure, the rate of myogenic correction of RBF is inhibited by 75% in βENaC m/m mice. These findings demonstrate that myogenic constriction in afferent arterioles is dependent on normal expression of βENaC.

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Abstract 060: POLDIP-2/NOX-4 Generates Hydrogen Peroxide that Impairs Myogenic Response of Afferent Arterioles from Mice with the Reduced Renal Mass Model of Chronic Kidney Disease

Hypertension ◽

10.1161/hyp.66.suppl_1.060 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Lingli Li ◽

En Yin Lai ◽

Zaiming Luo ◽

Glenn Solis ◽

Kathy K Griendling ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Hydrogen Peroxide ◽

Kidney Disease ◽

Renal Mass ◽

Perfusion Pressure ◽

Myogenic Response ◽

Mass Model ◽

Afferent Arterioles ◽

Novel Targets ◽

Myogenic Responses

Background: Because we have found that myogenic contractions are stimulated by superoxide (O 2 .- ) but inhibited by hydrogen peroxide (H 2 O 2 ), we tested the hypothesis that H 2 O 2 is the cause of the impaired myogenic responses of afferent arterioles from mice with the reduced renal mass (RRM) model of chronic kidney disease (CKD). Methods: Mice were subjected to 5/6 surgical nephrectomy or sham operations and fed 6% salt for 3 months. Single afferent arterioles were perfused, their diameter measured directly and O 2 .- and H 2 O 2 measured by fluorescence microscopy. Results: The perfusion pressure of isolated afferent arterioles was increased from 40 to 80 mmHg to study myogenic responses. Arterioles from mice with RRM (vs sham) had a greater increase in O 2 .- (21.2 ± 1.9 versus 11.3 ± 2.5%; p < 0.01) and especially H 2 O 2 (28.7 ± 3.7 versus 4.2 ± 0.4%, P<0.005), but a reduction in myogenic contraction (-1.7 ± 4.3 versus -14.4 ± 3.6%; p < 0.005) . Myogenic contractions were paradoxically reversed in afferent arterioles from mice with RRM after reduction in O 2 .- by PEG-SOD (+3.3 ± 1.5 versus -1.7 ± 4.3%, P<0.05) or deletion of p47 phox (+2.5 ± 1.4 versus -1.7 ± 4.3%, P<0.05). In contrast, myogenic responses were increased even above the levels of shams in arterioles from mice with RRM after reduction in H 2 O 2 by PEG-catalase (-19.1 ± 1.6 versus -1.7 ± 4.3%, P<0.005) or transgenic overexpression of catalase in smooth muscle cells (-10.7 ± 1.3 versus -1.7 ± 4.3%, P<0.01). Gene expression for NOX-4 and POLDIP-2 (main source of H 2 O 2 ) was increased 40-50% (P<0.05) in individual afferent arterioles from mice with RRM. Moreover, the myogenic contractions in the arterioles from POLDIP-2+/- mice with RRM were similar to POLDIP-2+/- with sham operations (-7.7 ± 0.9 versus -8.0 ± 0.6, P=NS). Conclusions: Afferent arterioles from mice with RRM had severely impaired myogenic responses that were attributed to increased H 2 O 2 generation from POLDIP-2/NOX-4 that may therefore be novel targets to maintain autoregulation and protect kidneys from barotrauma in CKD.

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Soybean proteins counteract heart remodeling in wistar rats fed a high sodium chloride diet

Nephrology (Saint-Petersburg) ◽

10.36485/1561-6274-2019-236-92-99 ◽

2019 ◽

Vol 23 (6) ◽

pp. 92-99

Author(s):

I. G. Kayukov ◽

O. N. Beresneva ◽

M. M. Parastaeva ◽

G. T. Ivanova ◽

A. N. Kulikov ◽

...

Keyword(s):

Blood Pressure ◽

Sodium Chloride ◽

Cardiac Remodeling ◽

Wistar Rats ◽

Salt Intake ◽

Left Ventricular ◽

High Salt ◽

Soy Proteins ◽

High Sodium ◽

Heart Remodeling

BACKGROUND. Increased salt intake is associated with a number of cardiovascular events, including increased blood pressure (BP) and the development of left ventricular hypertrophy (LVH). However, there is much evidence that a high content of sodium chloride in the diet does not always lead to an increase in BP, but almost inevitably causes cardiac remodeling, in particular, LVH. Many aspects of myocardial remodeling induced by high sodium content in the food have not been studied enough. THE AIM of the study was to trace the echocardiographic changes in Wistar rats fed the high salt ration and the high salt ration supplemented with soy proteins.MATERIAL AND METHODS. Echocardiography and BP measurements were performed on male Wistar rats, divided into three groups. The first (control; n = 8) included rats that received standard laboratory feed (20.16 % animal protein and 0.34 % NaCl); the second (n = 10) – animals that received standard feed and 8 % NaCl (high salt ration). The third group (n = 10) consisted of rats who consumed a low-protein diet containing 10 % soy protein isolate (SUPRO 760) and 8 % NaCl. The follow-up period was 2 and 4 months.THE RESULTS of the study showed that: (1) the intake of a large amount of salt with a diet does not necessarily lead to the formation of arterial hypertension; (2) despite the absence of a distinct increase in BP, under these conditions signs of cardiac remodeling, in particular, LVH, appear rather quickly; (3) supplementing a high-salt diet with soy isolates counteracts the development of LVH.CONCLUSION. High salt intake with food can cause heart remodeling, regardless of blood pressure, while soy proteins can counteract this process.

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Physical Activity Modulates Blood Pressure Regulation During Controlled Low and High Salt Diets

Medicine & Science in Sports & Exercise ◽

10.1249/01.mss.0000535554.56458.d5 ◽

2018 ◽

Vol 50 (5S) ◽

pp. 142

Author(s):

Austin T. Robinson ◽

Kamila U. Migdal ◽

Matthew C. Babcock ◽

Joseph C. Watso ◽

Megan M. Wenner ◽

...

Keyword(s):

Physical Activity ◽

Blood Pressure ◽

Blood Pressure Regulation ◽

High Salt ◽

Pressure Regulation

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Selective neuronal nitric oxide synthase inhibition blocks furosemide-stimulated renin secretion in vivo

AJP Renal Physiology ◽

10.1152/ajprenal.1995.269.1.f134 ◽

1995 ◽

Vol 269 (1) ◽

pp. F134-F139 ◽

Cited By ~ 31

Author(s):

W. H. Beierwaltes

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Nitric Oxide Synthase ◽

Perfusion Pressure ◽

Renal Perfusion ◽

Macula Densa ◽

Renin Secretion ◽

Renal Perfusion Pressure ◽

Neuronal Nos ◽

Oxide Synthase

The macula densa is a regulatory site for renin. It contains exclusively the neuronal isoform of nitric oxide synthase (NOS), suggesting NO could stimulate renin secretion through the macula densa pathway. To test whether neuronal NOS mediates renin secretion, renin was stimulated by either the renal baroreceptor or the diuretic furosemide (acting through the macula densa pathway). Renin secretion rate (RSR) was measured in 12 Inactin-anesthetized rats at normal (104 +/- 3 mmHg) and reduced renal perfusion pressure (65 +/- 1 mmHg), before and after selective blockade of the neuronal NOS with 7-nitroindazole (7-NI, 50 mg/kg ip). 7-NI had no effect on basal blood pressure (102 +/- 2 mmHg) or renal blood flow (RBF). Decreasing renal perfusion pressure doubled RSR from 11.8 +/- 3.3 to 22.9 +/- 5.7 ng ANG I.h-1.min-1 (P < 0.01) (ANG I is angiotensin I). Similarly, in 7-NI-treated rats, reduced perfusion doubled RSR from 8.5 +/- 1.8 to 20.5 +/- 6.2 ng ANG I.h-1.min-1 (P < 0.01). Renal hemodynamics and RSR were measured in response to 5 mg/kg iv furosemide in 12 control rats and 11 rats treated with 7-NI. Blocking neuronal NOS did not alter blood pressure (102 +/- 2 mmHg), RBF (5.8 +/- 0.4 ml.min-1.g kidney wt-1), or renal vascular resistance (18.7 +/- 1.4 mmHg.ml-1.min.g kidney wt).(ABSTRACT TRUNCATED AT 250 WORDS)

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

International Journal of Molecular Sciences ◽

10.3390/ijms20143495 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3495 ◽

Cited By ~ 1

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.

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Different blood pressure responses in hypertensive rats following chemerin mRNA inhibition in dietary high fat compared to dietary high-salt conditions

Physiological Genomics ◽

10.1152/physiolgenomics.00050.2019 ◽

2019 ◽

Vol 51 (11) ◽

pp. 553-561 ◽

Cited By ~ 2

Author(s):

David J. Ferland ◽

Emma D. Flood ◽

Hannah Garver ◽

Steve T. Yeh ◽

Stanley Riney ◽

...

Keyword(s):

Blood Pressure ◽

Antisense Oligonucleotides ◽

Reduce Blood Pressure ◽

High Salt ◽

Whole Body ◽

Sprague Dawley ◽

High Fat ◽

Hypertensive Rats ◽

Blood Pressure Responses ◽

Antihypertensive Treatments

Chemerin is a contractile adipokine, produced in liver and fat, and removal of the protein by antisense oligonucleotides (ASO) lowers blood pressure in the normal Sprague Dawley rat. In humans, chemerin is positively associated with blood pressure and obesity so we hypothesized that in a model of hypertension derived from high-fat (HF) feeding, the chemerin ASO would reduce blood pressure more than a high-salt (HS) model. Male Dahl S rats were given a HF (60% kcal fat; age 3–24 wk) or HS diet (4% salt; age 20–24 wk to match age and blood pressure of HF animals). Scrambled control, whole body, or liver-specific ASOs that knock down chemerin were delivered subcutaneously once per week for 4 wk with tissue and blood collected 2 days after the last injection. Conscious blood pressure was measured 24 h/day by radiotelemetry. By the end of whole body ASO administration, blood pressure of HF animals had fallen 29 ± 2 mmHg below baseline, while blood pressure of HS-diet animals fell by only 12 ± 4 mmHg below baseline. Administration of a liver-specific ASO to HF Dahl S resulted in a 6 ± 2 mmHg fall in blood pressure below baseline. Successful knockdown of chemerin in both the whole body and liver-specific administration was confirmed by Western and PCR. These results suggest that chemerin, not derived from liver but potentially from adipose tissue, is an important driver of hypertension associated with high fat. This knowledge could lead to the development of antihypertensive treatments specifically targeted to obesity-associated hypertension.

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