Abstract 101: Tissue-specific Deletion of Collectrin in the Proximal Tubular Epithelium Increases Arterial Pressure and Augments Salt-sensitivity

Background: Collectrin ( Tmem27 ) is a key regulator of blood pressure (BP) and modulator of the bioavailability of nitric oxide (NO) and superoxide. It is highly expressed in the kidney in the proximal tubule (PT), collecting duct, and throughout the vascular endothelium. We reported that collectrin plays a critical role as a chaperone for the reabsorption of all amino acids (AAs) in the PT, and for the uptake of the cationic AA L-arginine (L-Arg) in endothelial cells. Global collectrin knockout ( Tmem27 Y/- ) mice display baseline hypertension (HTN), augmented salt-sensitive hypertension (SSH), and decreased renal blood flow. Objective and Methods: To determine the PT-specific effect of collectrin on BP homeostasis and salt sensitivity, we used the Cre -loxP approach and PEPCK-Cre to generate a mouse line lacking collectrin specifically in the PT-- PEPCK-Cre + Tmem27 Y/Flox mice. PEPCK-Cre - Tmem27 Y/Flox mice were used as control. Radiotelemetry was used to measure BP for 2 weeks at baseline and 2 weeks on high salt diet (HSD). Renal blood flow at baseline and on HSD was measured using contrast enhanced ultrasound in the same mice. Results: Successful deletion of collectrin in the PT was confirmed by assessing mRNA levels using real-time RT-PCR, immunohistochemistry staining of renal tissues using anti-collectrin antibody, and quantitation of protein from kidney cortex by Western analysis. Compared to control PEPCK-Cre - Tmem27 Y/Flox mice (n=6), PEPCK-Cre + Tmem27 Y/Flox mice (n=6) displayed significantly higher systolic BP (SBP) at baseline (120.0 ± 2.5 vs 131.6 ± 2.9 mm Hg; p = 0.014) and after HSD (135.3 ± 2.6 vs 151.5 ± 5.2 mm Hg; p = 0.019). Renal blood flow was not different between groups, at baseline nor after HSD. Conclusion: Collectrin in the PT plays an important role in blood pressure homeostasis and response to sodium intake, independent of renal blood flow. Increasing proximal tubular collectrin activity may be a novel therapeutic strategy for the treatment of hypertension and salt-sensitivity.

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Renal blood flow, early distal sodium, and plasma renin concentrations during osmotic diuresis

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2000.279.4.r1268 ◽

2000 ◽

Vol 279 (4) ◽

pp. R1268-R1276 ◽

Cited By ~ 20

Author(s):

Paul P. Leyssac ◽

Niels-Henrik Holstein-Rathlou ◽

Ole Skøtt

Keyword(s):

Blood Flow ◽

Renal Blood Flow ◽

Sodium Excretion ◽

Plasma Renin ◽

Urine Flow ◽

Sodium Reabsorption ◽

Osmotic Diuresis ◽

Nacl Concentration ◽

Proximal Tubular ◽

Distal Tubules

Inconsistencies in previous reports regarding changes in early distal NaCl concentration (EDNaCl) and renin secretion during osmotic diuresis motivated our reinvestigation. After intravenous infusion of 10% mannitol, EDNaCl fell from 42.6 to 34.2 mM. Proximal tubular pressure increased by 12.6 mmHg. Urine flow increased 10-fold, and sodium excretion increased by 177%. Plasma renin concentration (PRC) increased by 58%. Renal blood flow and glomerular filtration rate decreased, however end-proximal flow remained unchanged. After a similar volume of hypotonic glucose (152 mM), EDNaClincreased by 3.6 mM, ( P < 0.01) without changes in renal hemodynamics, urine flow, sodium excretion rate, or PRC. Infusion of 300 μmol NaCl in a smaller volume caused EDNaCl to increase by 6.4 mM without significant changes in PRC. Urine flow and sodium excretion increased significantly. There was a significant inverse relationship between superficial nephron EDNaCl and PRC. We conclude that EDNa decreases during osmotic diuresis, suggesting that the increase in PRC was mediated by the macula densa. The results suggest that the natriuresis during osmotic diuresis is a result of impaired sodium reabsorption in distal tubules and collecting ducts.

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Hypothalamic paraventricular nucleus is critical for renal vasoconstriction elicited by elevations in body temperature

AJP Renal Physiology ◽

10.1152/ajprenal.00488.2007 ◽

2008 ◽

Vol 294 (2) ◽

pp. F309-F315 ◽

Cited By ~ 12

Author(s):

Joo Lee Cham ◽

Emilio Badoer

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Blood Flow ◽

Renal Blood Flow ◽

Core Temperature ◽

Paraventricular Nucleus ◽

Hypothalamic Paraventricular Nucleus ◽

Body Core Temperature ◽

Control Group ◽

Body Core

Redistribution of blood from the viscera to the peripheral vasculature is the major cardiovascular response designed to restore thermoregulatory homeostasis after an elevation in body core temperature. In this study, we investigated the role of the hypothalamic paraventricular nucleus (PVN) in the reflex decrease in renal blood flow that is induced by hyperthermia, as this brain region is known to play a key role in renal function and may contribute to the central pathways underlying thermoregulatory responses. In anesthetized rats, blood pressure, heart rate, renal blood flow, and tail skin temperature were recorded in response to elevating body core temperature. In the control group, saline was microinjected bilaterally into the PVN; in the second group, muscimol (1 nmol in 100 nl per side) was microinjected to inhibit neuronal activity in the PVN; and in a third group, muscimol was microinjected outside the PVN. Compared with control, microinjection of muscimol into the PVN did not significantly affect the blood pressure or heart rate responses. However, the normal reflex reduction in renal blood flow observed in response to hyperthermia in the control group (∼70% from a resting level of 11.5 ml/min) was abolished by the microinjection of muscimol into the PVN (maximum reduction of 8% from a resting of 9.1 ml/min). This effect was specific to the PVN since microinjection of muscimol outside the PVN did not prevent the normal renal blood flow response. The data suggest that the PVN plays an essential role in the reflex decrease in renal blood flow elicited by hyperthermia.

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Effect of chloride on renal blood flow in angiotensin II induced hypertension

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y91-076 ◽

1991 ◽

Vol 69 (4) ◽

pp. 507-511 ◽

Cited By ~ 5

Author(s):

John C. Passmore ◽

Agnes E. Jimenez

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Sodium Chloride ◽

Angiotensin Ii ◽

Renal Blood Flow ◽

Dietary Sodium ◽

Maximum Increase ◽

High Sodium ◽

Low Sodium ◽

Chloride Effect

The effect of selective dietary sodium and (or) chloride loading on blood pressure and renal blood flow (RBF) in the rat angiotensin II (AII) model of hypertension was determined. AII (200 ng/min) or saline was infused intraperitoneally. Diets were provided with either high or low concentrations of sodium, chloride or both ions for 22 days. The blood pressure of saline-treated animals was not increased by the high sodium chloride diet. Animals on a high sodium, high chloride diet had a significantly greater increase of blood pressure at 8, 15, 18, and 22 days of AII infusion compared with AII-treated animals on a low sodium, low chloride diet (p < 0.05). Selective dietary loading of either high sodium or chloride in AII-treated rats produced no greater elevation of blood pressure than AII with the low sodium, low chloride diet. Selective high dietary chloride was associated with a lower RBF in AII- and vehicle-treated rats compared with low dietary chloride. The chloride effect on RBF was greater in AII-treated animals. In conclusion, both sodium and chloride are necessary to produce the maximum increase of blood pressure in AII animals. AII enhances the decreased RBF induced by dietary chloride.Key words: angiotensin II, sodium chloride, blood pressure.

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Effects of l-arginine on systemic and renal haemodynamics in conscious dogs

Clinical Science ◽

10.1042/cs0810727 ◽

1991 ◽

Vol 81 (6) ◽

pp. 727-732 ◽

Cited By ~ 18

Author(s):

Marohito Murakami ◽

Hiromichi Suzuki ◽

Atsuhiro Ichihara ◽

Mareo Naitoh ◽

Hidetomo Nakamoto ◽

...

Keyword(s):

Blood Pressure ◽

Heart Rate ◽

Blood Flow ◽

Renal Blood Flow ◽

Arterial Blood Pressure ◽

Mean Arterial Blood Pressure ◽

Renal Haemodynamics ◽

Conscious Dogs ◽

Arginine Infusion ◽

Arterial Blood

1. The effects of l-arginine on systemic and renal haemodynamics were investigated in conscious dogs. l-Arginine was administered intravenously at doses of 15 and 75 μmol min−1 kg−1 for 20 min. 2. Mean arterial blood pressure, heart rate and cardiac output were not changed significantly by l-arginine infusion. However, l-arginine infusion induced a significant elevation of renal blood flow from 50 ± 3 to 94 ± 12 ml/min (means ± sem, P < 0.01). 3. Simultaneous infusion of NG-monomethyl-l-arginine (0.5 μmol min−1 kg−1) significantly inhibited the increase in renal blood flow produced by l-arginine (15 μmol min−1 kg−1) without significant changes in mean arterial blood pressure or heart rate. 4. Pretreatment with atropine completely inhibited the l-arginine-induced increase in renal blood flow, whereas pretreatment with indomethacin attenuated it (63 ± 4 versus 82 ± 10 ml/min, P < 0.05). 5. A continuous infusion of l-arginine increased renal blood flow in the intact kidney (55 ± 3 versus 85 ± 9 ml/min, P < 0.05), but not in the contralateral denervated kidney (58 ± 3 versus 56 ± 4 ml/min, P > 0.05). 6. These results suggest that intravenously administered l-arginine produces an elevation of renal blood flow, which may be mediated by facilitation of endogenous acetylcholine-induced release of endothelium-derived relaxing factor and vasodilatory prostaglandins.

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HYPERTENSION AS A REACTION PATTERN TO STRESS; SUMMARY OF EXPERIMENTAL DATA ON VARIATIONS IN BLOOD PRESSURE AND RENAL BLOOD FLOW

Annals of Internal Medicine ◽

10.7326/0003-4819-29-6-1056 ◽

1948 ◽

Vol 29 (6) ◽

pp. 1056 ◽

Cited By ~ 67

Keyword(s):

Experimental Data ◽

Blood Pressure ◽

Blood Flow ◽

Renal Blood Flow ◽

Reaction Pattern

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Detection of 3rd mechanism in renal blood flow via high‐resolution, time‐varying spectral analysis of records subjected to chirp forcing of blood pressure

The FASEB Journal ◽

10.1096/fasebj.22.1_supplement.761.15 ◽

2008 ◽

Vol 22 (S1) ◽

Author(s):

Kin Siu ◽

Catherine Lau ◽

William Cupples ◽

Ki Chon

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Spectral Analysis ◽

High Resolution ◽

Renal Blood Flow ◽

Time Varying ◽

Resolution Time

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Abstract 1785: Renal Artery Angioplasty Improves Diastolic Cardiac Function In Patients With heart failure Possessing Renal Artery Stenosis.

Circulation ◽

10.1161/circ.116.suppl_16.ii_379 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Eisei Yamamoto ◽

Hitoshi Takano ◽

Hiroyuki Tajima ◽

Jun Tanabe ◽

Hidekazu Kawanaka ◽

...

Keyword(s):

Heart Failure ◽

Blood Pressure ◽

Blood Flow ◽

Cardiac Function ◽

Renal Artery ◽

Renal Blood Flow ◽

Renal Artery Stenosis ◽

Arterial Blood Pressure ◽

Arterial Blood ◽

Diastolic Cardiac Function

Background: Renal artery stenosis (RAS) often plays an important role not only in malignant hypertension but also in sudden development of heart failure (HF) so called ‘flash pulmonary edema’ or chronic HF refractory to medical treatment. One of the possible mechanisms whereby RAS affects these unique conditions of HF is suppression of LV compliance through the complex interaction between neurohormonal systems originating from the reduction of renal blood flow. Renal artery angioplasty is expected to be an effective treatment for restoring renal blood flow in patients with RAS. The aim of the present study was whether the angioplasty can improve the impaired neurohormonal systems and diastolic cardiac function in patients with RAS. Methods: A prospective analysis was performed in 18 HF patients with RAS (age: 72±6, 3 females, NYHA I/II/III: 5/9/4) who underwent renal artery angioplasty between 2005 and 2007. Four patients with significant bilateral RAS and 3 patients with unilateral RAS in the vessel supplying a functional solitary kidney were included. We monitored the changes of biochemical and neurohormonal markers and blood pressure. Cardiac function was evaluated by tissue Doppler echocardiogram before and 3 months after the procedure. Results: Technical success was achieved in all interventions. The results are shown in table . Systolic arterial blood pressure significantly decreased by renal angioplasty. B-type natriuretic peptide (BNP) was significantly reduced 3 months after the angioplasty, whereas the change of sCr or angiotensinII was not statistically significant. Myocardial early diastolic velocity (Em), a parameter of diastolic LV function, was significantly improved compared with that measured before the procedure. Conclusions: In patients with either overt or latent HF possessing RAS, renal artery angioplasty not only decreases arterial blood pressure but also improves diastolic cardiac function in parallel with the reduction of BNP level.

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Abstract 196: Role of Collecting Duct Renin in Blood Pressure Regulation

Hypertension ◽

10.1161/hyp.62.suppl_1.a196 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Nirupama Ramkumar ◽

Deborah Stuart ◽

Sara Rees ◽

Curt Sigmund ◽

Donald E Kohan

Keyword(s):

Blood Pressure ◽

Collecting Duct ◽

Dna Recombination ◽

Plasma Renin ◽

Blood Pressure Regulation ◽

P System ◽

Mrna Levels ◽

Pressure Regulation ◽

Renin Mrna ◽

Exon 1

Recent studies propose that collecting duct (CD) renin is an important modulator of blood pressure regulation, especially in conditions such as angiotensin-II infused hypertension. We used gene targeting to generate a CD-specific renin knockout (KO) to assess if CD derived renin can regulate BP. Utilizing the Cre lox P system, exon 1 of the renin gene was ablated specifically in the CD. BP was recorded via telemetry and plasma and urine were collected in metabolic cages on normal, high and low Na diets. DNA recombination showed kidney specific recombination in KO mice. Compared to floxed mice, CD renin KO mice had 70 % lower medullary renin mRNA levels and 90% lower renin mRNA in micro-dissected cortical and inner medullary CD tubules. Urinary renin levels were significantly lower in the KO mice on normal and low Na diets (45% of floxed levels) but not with high Na intake. Plasma renin concentration was significantly higher in the KO mice on all three diets. While BP was similar between the two groups on all three diets, infusion of Ang-II delayed the increase in BP in the CD renin KO group for at least 4 days post-infusion. These findings suggest that CD renin likely plays a role in normal BP regulation (evidenced by an increase in PRC) and in response to AngII infusion.

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