Plasma and Renal Prorenin/Renin, Renin mRNA, and Blood Pressure in Dahl Salt-Sensitive and Salt-Resistant Rats

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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Interrelation between renin mRNA levels, renin secretion, and blood pressure in two-kidney, one clip rats.

Hypertension ◽

10.1161/01.hyp.24.2.157 ◽

1994 ◽

Vol 24 (2) ◽

pp. 157-162 ◽

Cited By ~ 20

Author(s):

K Schricker ◽

S Holmer ◽

M Hamann ◽

G Riegger ◽

A Kurtz

Keyword(s):

Blood Pressure ◽

Renin Secretion ◽

Mrna Levels ◽

Renin Mrna

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Effects of angiotensin II on remodelling of the airway and the vasculature in the rat

Clinical Science ◽

10.1042/cs0980001 ◽

1999 ◽

Vol 98 (1) ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Scott G. RAMSAY ◽

Christopher J. KENYON ◽

Niall WHYTE ◽

Ian C. MCKAY ◽

Neil C. THOMSON ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Young Male ◽

Renin Angiotensin System ◽

Mesenteric Arteries ◽

Airway Remodelling ◽

Cell Nuclei ◽

Renin Mrna ◽

Male Wistar Rats ◽

Post Infusion

Airway remodelling occurs in chronic asthma. Angiotensin II promotes growth in cardiovascular remodelling. Since the renin–angiotensin system is activated in acute severe asthma, we hypothesized that angiotensin II has a role in airway remodelling. A total of 14 young male Wistar rats were randomly divided into two groups. All received 2-week infusions of bromodeoxyuridine, and the experimental group also received angiotensin II. Blood pressure rose in the angiotensin II-infused group [mean levels: pre-infusion, 134.9 (S.D. 14.7) mmHg; post-infusion, 197.1 (22.5) mmHg], and expression of renin mRNA in the renal juxtaglomerular cells was suppressed in these animals. The proportion of bromodeoxyuridine-positive cell nuclei was no different in the airways of control and angiotensin II-infused animals for smooth muscle [mean bromodeoxyuridine index: control, 8.6% (S.E.M. 1.1%); angiotensin II, 9.3% (1.1%)], epithelium [control, 16.7% (2.3%); angiotensin II, 16.0% (2.2%)] and adventitia [control, 26.4% (2.2%); angiotensin II, 26.6% (2.4%)]. In the arteries, bromodeoxyuridine indices were higher in the angiotensin II-infused rats [18.4% (2.3%)] than in the control animals [9.4% (2.8%)], but no difference was found in the veins [12% (2.9%) and 11.4% (2.6%) respectively]. Morphometry of the airway wall and mesenteric vasculature was no different in the two groups. Therefore a 2-week infusion of angiotensin II increases blood pressure and DNA synthesis in the mesenteric arteries, but does not cause airway remodelling, in the rat.

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Endothelin-1 increases calcium and attenuates renin gene expression in As4.1 cells

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00295.2002 ◽

2002 ◽

Vol 283 (6) ◽

pp. H2458-H2465 ◽

Cited By ~ 16

Author(s):

Michael J. Ryan ◽

Thomas A. Black ◽

Susan L. Millard ◽

Kenneth W. Gross ◽

George Hajduczok

Keyword(s):

Blood Pressure ◽

Inositol Phosphates ◽

Nitric Oxide Donor ◽

Luciferase Reporter ◽

Reporter System ◽

Endothelin 1 ◽

Renin Gene ◽

Renin Mrna ◽

Potent Vasoconstrictor ◽

Endothelin 3

Endothelin-1 (ET-1) is a potent vasoconstrictor and blood pressure modulator. Renin secretion from juxtaglomerular (JG) cells is crucial for blood pressure and electrolyte homeostasis and has been shown to be modulated by ET-1; however, the cellular and molecular mechanism of this regulation is not clear. The purpose of this study was to gain a better understanding of the cellular and molecular pathways activated by ET-1 by using a renin-producing cell line As4.1. ET-1 caused an increase in As4.1 cell intracelluar Ca2+ concentration ([Ca2+]i) mediated by the ETAreceptor as its antagonist, BQ-123, abolished the response. The nitric oxide donor nitroprusside, but not 8-bromo-cGMP, reduced the time necessary for successive ET-1 responses. Endothelin-3 had no effect on [Ca2+]i. ET-1 dose dependently increased total inositol phosphates with an EC50 of 2.1 nM. ET-1 reduced renin mRNA by 68% independently of changes in message decay. With the use of a renin-luciferase reporter system in As4.1 cells, ET-1 reduced luciferase activity by 51%, suggesting that renin gene transcription is directly modified by ET-1.

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Knockout of Na+-glucose cotransporter SGLT1 mitigates diabetes-induced upregulation of nitric oxide synthase NOS1 in the macula densa and glomerular hyperfiltration

AJP Renal Physiology ◽

10.1152/ajprenal.00120.2019 ◽

2019 ◽

Vol 317 (1) ◽

pp. F207-F217 ◽

Cited By ~ 11

Author(s):

Panai Song ◽

Winnie Huang ◽

Akira Onishi ◽

Rohit Patel ◽

Young Chul Kim ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Gene Knockout ◽

Macula Densa ◽

Wild Type ◽

Kidney Weight ◽

Renin Mrna ◽

Sglt2 Inhibition ◽

Glomerular Size ◽

Akita Mice

Na+-glucose cotransporter (SGLT)1 mediates glucose reabsorption in late proximal tubules. SGLT1 also mediates macula densa (MD) sensing of an increase in luminal glucose, which increases nitric oxide (NO) synthase 1 (MD-NOS1)-mediated NO formation and potentially glomerular filtratrion rate (GFR). Here, the contribution of SGLT1 was tested by gene knockout (−/−) in type 1 diabetic Akita mice. A low-glucose diet was used to prevent intestinal malabsorption in Sglt1−/− mice and minimize the contribution of intestinal SGLT1. Hyperglycemia was modestly reduced in Sglt1−/− versus littermate wild-type Akita mice (480 vs. 550 mg/dl), associated with reduced diabetes-induced increases in GFR, kidney weight, glomerular size, and albuminuria. Blunted hyperfiltration was confirmed in streptozotocin-induced diabetic Sglt1−/− mice, associated with similar hyperglycemia versus wild-type mice (350 vs. 385 mg/dl). Absence of SGLT1 attenuated upregulation of MD-NOS1 protein expression in diabetic Akita mice and in response to SGLT2 inhibition in nondiabetic mice. During SGLT2 inhibition in Akita mice, Sglt1−/− mice had likewise reduced blood glucose (200 vs. 300 mg/dl), associated with lesser MD-NOS1 expression, GFR, kidney weight, glomerular size, and albuminuria. Absence of Sglt1 in Akita mice increased systolic blood pressure, associated with suppressed renal renin mRNA expression. This may reflect fluid retention due to blunted hyperfiltration. SGLT2 inhibition prevented the blood pressure increase in Sglt1−/− Akita mice, possibly due to additive glucosuric/diuretic effects. The data indicate that SGLT1 contributes to diabetic hyperfiltration and limits diabetic hypertension. Potential mechanisms include its role in glucose-driven upregulation of MD-NOS1 expression. This pathway may increase GFR to maintain volume balance when enhanced MD glucose delivery indicates upstream saturation of SGLTs and thus hyperreabsorption.

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A role for tubular Na+/H+ exchanger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin

AJP Renal Physiology ◽

10.1152/ajprenal.00264.2020 ◽

2020 ◽

Vol 319 (4) ◽

pp. F712-F728 ◽

Cited By ~ 2

Author(s):

Akira Onishi ◽

Yiling Fu ◽

Rohit Patel ◽

Manjula Darshi ◽

Maria Crespo-Masip ◽

...

Keyword(s):

Blood Pressure ◽

Sglt2 Inhibitor ◽

Urine Ph ◽

Expression Of Genes ◽

Urinary Glucose ◽

Renin Mrna ◽

Proximal Tubular ◽

Urine Composition ◽

Natriuretic Effect ◽

Akita Mice

Inhibitors of proximal tubular Na+-glucose cotransporter 2 (SGLT2) are natriuretic, and they lower blood pressure. There are reports that the activities of SGLT2 and Na+-H+ exchanger 3 (NHE3) are coordinated. If so, then part of the natriuretic response to an SGLT2 inhibitor is mediated by suppressing NHE3. To examine this further, we compared the effects of an SGLT2 inhibitor, empagliflozin, on urine composition and systolic blood pressure (SBP) in nondiabetic mice with tubule-specific NHE3 knockdown (NHE3-ko) and wild-type (WT) littermates. A single dose of empagliflozin, titrated to cause minimal glucosuria, increased urinary excretion of Na+ and bicarbonate and raised urine pH in WT mice but not in NHE3-ko mice. Chronic empagliflozin treatment tended to lower SBP despite higher renal renin mRNA expression and lowered the ratio of SBP to renin mRNA, indicating volume loss. This effect of empagliflozin depended on tubular NHE3. In diabetic Akita mice, chronic empagliflozin enhanced phosphorylation of NHE3 (S552/S605), changes previously linked to lesser NHE3-mediated reabsorption. Chronic empagliflozin also increased expression of genes involved with renal gluconeogenesis, bicarbonate regeneration, and ammonium formation. While this could reflect compensatory responses to acidification of proximal tubular cells resulting from reduced NHE3 activity, these effects were at least in part independent of tubular NHE3 and potentially indicated metabolic adaptations to urinary glucose loss. Moreover, empagliflozin increased luminal α-ketoglutarate, which may serve to stimulate compensatory distal NaCl reabsorption, while cogenerated and excreted ammonium balances urine losses of this “potential bicarbonate.” The data implicate NHE3 as a determinant of the natriuretic effect of empagliflozin.

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Early co-expression of cyclooxygenase-2 and renin in the rat kidney cortex contributes to the development of NG-nitro-l-arginine methyl ester induced hypertension

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2014-0347 ◽

2015 ◽

Vol 93 (4) ◽

pp. 299-308 ◽

Cited By ~ 5

Author(s):

Elizabeth Alejandrina Guzmán-Hernández ◽

Rafael Villalobos-Molina ◽

María Alicia Sánchez-Mendoza ◽

Leonardo Del Valle-Mondragón ◽

Gustavo Pastelín-Hernández ◽

...

Keyword(s):

Blood Pressure ◽

Methyl Ester ◽

Rat Kidney ◽

Cyclooxygenase 2 ◽

Kidney Cortex ◽

Ang Ii ◽

Rat Kidney Cortex ◽

Induced Hypertension ◽

Renin Mrna ◽

Cox 2

We investigated the involvement of cyclooxygenase-2 (COX-2) and the renin–angiotensin system in NG-nitro-l-arginine methyl ester (l-NAME)-induced hypertension. Male Wistar rats were treated with l-NAME (75.0 mg·(kg body mass)−1·day−1, in their drinking water) for different durations (1–33 days). COX-2 and renin mRNA were measured using real-time PCR in the renal cortex, and prostanoids were assessed in the renal perfusate, whereas angiotensin II (Ang II) and Ang (1-7) were quantified in plasma. In some rats, nitric oxide synthase inhibition was carried out in conjunction with oral administration of captopril (30.0 mg·kg−1·day−1) or celecoxib (1.0 mg·kg−1·day−1) for 2 or 19 days. We found a parallel increase in renocortical COX-2 and renin mRNA starting at day 2 of treatment with l-NAME, and both peaked at 19–25 days. In addition, l-NAME increased renal 6-Keto-PGF1α (prostacyclin (PGI2) metabolite) and plasma Ang II from day 2, but reduced plasma Ang (1-7) at day 19. Captopril prevented the increase in blood pressure, which was associated with lower plasma Ang II and increased COX-2-derived 6-Keto-PGF1α at day 2 and plasma Ang (1-7) at day 19. Celecoxib partially prevented the increase in blood pressure; this effect was associated with a reduction in plasma Ang II. These findings indicate that renal COX-2 expression increased in parallel with renin expression, renal PGI2 synthesis, and plasma Ang II in l-NAME-induced hypertension.

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Transcriptional regulator RBP-J regulates the number and plasticity of renin cells

Physiological Genomics ◽

10.1152/physiolgenomics.00061.2011 ◽

2011 ◽

Vol 43 (17) ◽

pp. 1021-1028 ◽

Cited By ~ 47

Author(s):

Ruth M. Castellanos Rivera ◽

Maria C. Monteagudo ◽

Ellen S. Pentz ◽

Sean T. Glenn ◽

Kenneth W. Gross ◽

...

Keyword(s):

Blood Pressure ◽

Conditional Knockout ◽

Cell Phenotype ◽

Mrna Levels ◽

Downstream Effector ◽

Notch Receptors ◽

Severe Reduction ◽

Renin Mrna ◽

Afferent Arterioles ◽

The Common

Renin-expressing cells are crucial in the control of blood pressure and fluid-electrolyte homeostasis. Notch receptors convey cell-cell signals that may regulate the renin cell phenotype. Because the common downstream effector for all Notch receptors is the transcription factor RBP-J, we used a conditional knockout approach to delete RBP-J in cells of the renin lineage. The resultant RBP-J conditional knockout (cKO) mice displayed a severe reduction in the number of renin-positive juxtaglomerular apparatuses (JGA) and a reduction in the total number of renin positive cells per JGA and along the afferent arterioles. This reduction in renin protein was accompanied by a decrease in renin mRNA expression, decreased circulating renin, and low blood pressure. To investigate whether deletion of RBP-J altered the ability of mice to increase the number of renin cells normally elicited by a physiological threat, we treated RBP-J cKO mice with captopril and sodium depletion for 10 days. The resultant treated RBP-J cKO mice had a 65% reduction in renin mRNA levels (compared with treated controls) and were unable to increase circulating renin. Although these mice attempted to increase the number of renin cells, the cells were unusually thin and had few granules and barely detectable amounts of immunoreactive renin. As a consequence, the cells were incapable of fully adopting the endocrine phenotype of a renin cell. We conclude that RBP-J is required to maintain basal renin expression and the ability of smooth muscle cells along the kidney vasculature to regain the renin phenotype, a fundamental mechanism to preserve homeostasis.

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