Lisa Harrison-bernard - Academia.edu (original) (raw)

Papers by Lisa Harrison-bernard

The Ochsner journal, 2013

Diabetic nephropathy (DN) is associated with enhanced renal, plasma, and urinary endothelin (ET)-... more Diabetic nephropathy (DN) is associated with enhanced renal, plasma, and urinary endothelin (ET)-1 levels. Chymase cleaves Big ET-1 (1-38) to ET-1 (1-31), which is further cleaved by neutral endopeptidase to ET-1 (1-21). The current study tested the hypothesis that afferent arterioles (AA) of diabetic kidneys exhibit enhanced vasoconstrictor responses to chymase-dependent intrarenal ET formation compared to control kidneys. In situ juxtamedullary AA vasoconstrictor responses to the intrarenal conversion of Big ET-1 (1-38) to ET-1 (1-21) were performed in the absence and presence of chymase inhibition in type 2 diabetic db/db and control db/m mice studied under in vitro experimental conditions. AA vasoconstrictor responses to Big ET-1 (1-38) were significantly enhanced in diabetic compared to control kidneys. In the presence of chymase inhibition (JNJ-18054478), AA vasoconstrictor responses of diabetic kidneys to Big ET-1 (1-38) were significantly less than the responses of control k...

C ardiovascular diseases are the leading cause of death in women and claim the lives of more than... more C ardiovascular diseases are the leading cause of death in women and claim the lives of more than half a million women every year. The incidence of cardiovascular disease is 4-fold higher in postmenopausal women than in women of the same age who are premenopausal. 1 Hypertension is a major risk factor for cardiovascular disease. It has been shown that after adjustment for age and body mass index, postmenopausal women are more than twice as likely to be hypertensive as premenopausal women. 2 Evidence that hypertensive postmenopausal women are more salt-sensitive than normotensive postmenopausal women 3 suggests that decreases in ovarian hormone levels and increased sensitivity to dietary sodium may be important factors in the genesis of postmenopausal hypertension. Thus, after menopause, hypertension may contribute to the increase in cardiovascular risk of postmenopausal women. The mechanisms responsible for the increase in blood pressure after menopause are still under investigation. In the United States alone, Ϸ38% of postmenopausal, 6 or 10 million, women use some form of hormone replacement therapy. There is quite a bit of controversy over the cardiovascular health benefits of estrogen replacement therapy, especially in light of the cessation of the estrogen-alone component of the National Heart, Lung and Blood Institutefunded Women's Health Initiative (WHI) hormone trial earlier this year. Results of the nearly 7-year follow-up of 11 000 healthy postmenopausal women using conjugated equine estrogen or placebo who had a hysterectomy showed an increased risk of stroke and no reduction in the risk of coronary heart disease. 7 Additionally, the estrogen plus progestin trial of the WHI had been stopped 2 years earlier when an increased risk of breast cancer, heart disease, stroke, and blood clots were determined to outweigh the benefits of reduced risks of hip fracture and colorectal cancer in women who had a uterus. These studies have sparked a worldwide scare over the risks of hormone replacement therapy. However, potential flaws in the study should be noted in that the subjects in the WHI trial were in their 60s and early 70s and had long since gone through menopause and may have had asymptomatic cardiovascular disease (or atherosclerosis) when the study was initiated. Additionally, these clinical studies did not address a role for modulation of the renin-angiotensin system by estrogen. Therefore, there continues to be a need for continued basic research and new clinical trials on the cardiovascular effects of hormone replacement therapy.

American Journal of Physiology - Renal Physiology, 2015

Journal of Investigative Medicine, 2013

Journal of the American Society of Nephrology

Chronic elevations in circulating angiotensin II (AngII) levels produce sustained hypertension an... more Chronic elevations in circulating angiotensin II (AngII) levels produce sustained hypertension and increased intrarenal AngII contents through multiple mechanisms, which may include sustained or increased local production of AngII. This study was designed to test the hypothesis that chronic AngII infusion increases renal angiotensinogen mRNA and protein levels, thus contributing to the increase in intrarenal AngII levels. AngII (80 ng/min) was infused subcutaneously for 13 d into Sprague-Dawley rats, using osmotic minipumps. Control rats underwent sham operations. By day 12, systolic arterial BP increased to 184 ± 3 mmHg in AngII-treated rats, whereas values for sham-treated rats remained at control levels (125 ± 1 mmHg). Plasma renin activity was markedly suppressed (0.2 ± 0.1 versus 5.3 ± 1.2 ng AngI/ml per h); however, renal AngII contents were significantly increased in AngII-treated rats (273 ± 29 versus 99 ± 18 fmol/g). Western blot analyses of plasma and liver protein using a polyclonal anti-angiotensinogen antibody demonstrated two specific immunoreactive bands, at 52 and 64 kD, whereas kidney tissue exhibited one band, at 52 kD. Densitometric analyses demonstrated that AngII infusion did not alter plasma (52-or 64-kD), renal (52-kD), or hepatic (52-kD) angiotensinogen protein levels; however, there was a significant increase in hepatic expression of the highly glycosylated 64-kD angiotensinogen protein, of almost fourfold (densitometric value/ control value ratios of 3.79 ± 1.16 versus 1.00 ± 0.35). Renal and hepatic expression of angiotensinogen mRNA, which was examined by semiquantitative reverse transcription-PCR, was significantly increased in AngII-treated rats, compared with sham-treated rats (kidney, densitometric value/glyceraldehyde-3-phosphate dehydrogenase mRNA value ratios of 0.82 ± 0.11 versus 0.58 ± 0.04; liver, densitometric value/glyceraldehyde-3-phosphate dehydrogenase mRNA value ratios of 2.34 ± 0.07 versus 1.32 ± 0.15). These results indicate that increases in circulating AngII levels increase intrarenal angiotensinogen mRNA levels, which may contribute to the sustained renal AngIIgenerating capacity that paradoxically occurs in AngII-treated hypertensive rats.

Aberrant gene-environment interactions are implicated in the pathogenesis of congenital renal dys... more Aberrant gene-environment interactions are implicated in the pathogenesis of congenital renal dysgenesis (CRD), a leading cause of renal failure in infants and children. We have recently developed an animal model of CRD that is caused by gestational salt stress (5% NaCl diet; HS) of bradykinin B 2 R null mice (B 2 R-/- CRD ; Physiol. Genomics, 2000). Developing B 2 R-/-CRD mice exhibit tubular and glomerular cysts, stromal expansion and loss of cortico-medullary differentiation. In addition, B 2 R-/-CRD mice exhibit transient hypertension from 2-4 months of age. The present study was designed to determine the long-term consequences of CRD on renal morphology and salt sensitivity of blood pressure in B 2 R-/-CRD mice. One-year and 18 month old B 2 R-/-CRD mice exhibited stunted renal growth, glomerular cystic abnormalities and collecting duct ectasia. Moreover, tumors of mesenchymal cell origin emerged in the dysplastic kidneys of 90% of one-year old and 100% of 18-month-old B 2 R-/-CRD but not in age-matched B 2 R-/-or wild-type mice. When challenged with a HS diet, 18-month-old B 2 R-/-CRD exhibited a significant rise in systolic and diastolic blood pressures and more pronounced natriuresis and diuresis as compared to salt-loaded 18-month-old wild-type mice. Kidney aquaporin-2 expression was decreased by 50%, whereas renin, AT 1 receptor, and Na + -K + -ATPase levels were not different in B 2 R-/-CRD as compared to controls. In conclusion, this study demonstrates that B 2 R-/-CRD mice exhibit permanent phenotypic and functional abnormalities in renal growth and differentiation. This novel model of human disease links gene-environment interactions with renal development and blood pressure homeostasis.

American journal of physiology. Regulatory, integrative and comparative physiology, 2003

Physiological genomics, Jan 8, 2000

Congenital abnormalities of the kidney and urinary tract are a common cause of end-stage renal di... more Congenital abnormalities of the kidney and urinary tract are a common cause of end-stage renal disease in children. Host and environment factors are implicated in the pathogenesis of aberrant renal development. However, direct evidence linking gene-environment interactions with congenital renal disease is lacking. We report an animal model of renal dysgenesis that is dependent on a defined genetic defect and specific embryonic stressor. Specifically, mice that are deficient in the bradykinin type 2 receptor gene (B(2)) and salt loaded during embryogenesis acquire an aberrant kidney phenotype and die shortly after birth. In contrast, B(2) mutant mice maintained on normal sodium intake or salt-loaded wild-type mice do not develop kidney abnormalities. The kidney abnormality is evident histologically on embryonic day 16, shortly after the onset of metanephric B(2) gene expression, and consists of distorted renal architecture, foci of tubular dysgenesis, and cyst formation. The dysplast...

American Journal of Physiology - Renal Physiology, 2002

The relative contributions of AT(1A) and AT(1B) receptors to afferent arteriolar autoregulatory c... more The relative contributions of AT(1A) and AT(1B) receptors to afferent arteriolar autoregulatory capability and afferent and efferent arteriolar responses to ANG II are not known. Experiments were conducted in kidneys from wild-type (WT) and AT(1A)-/- mice utilizing the in vitro blood-perfused juxtamedullary nephron technique. Direct measurements of afferent (AAD) and efferent arteriolar diameters (EAD) were assessed at a renal arterial pressure of 100 mmHg. AAD averaged 14.8 +/- 0.8 microm for WT and 14.9 +/- 0.8 microm for AT(1A)-/- mice. AAD significantly decreased by 7 +/- 1, 16 +/- 1, and 26 +/- 2% for WT mice and by 11 +/- 1, 20 +/- 2, and 30 +/- 3% for AT(1A)-/- mice (120, 140, 160 mmHg). AAD autoregulatory capability was not affected by the absence of AT(1A) receptors. AAD responses to 10 nM ANG II were significantly blunted for AT(1A)-/- mice compared with WT (-22 +/- 2 vs. -37 +/- 5%). ANG II (0.1-10 nM) failed to elicit any change in EAD for AT(1A)-/- mice. AAD and EAD reductions in ANG II were blocked by 1 microM candesartan. We conclude that afferent arteriole vasoconstrictor responses to ANG II are mediated by AT(1A) and AT(1B) receptors, whereas efferent arteriolar vasoconstrictor responses to ANG II are mediated by only AT(1A) receptors in the mouse kidney.

American journal of hypertension, 2007

Rodents express two isoforms of the angiotensin II type 1 (AT(1)) receptor: AT(1A) and AT(1B). It... more Rodents express two isoforms of the angiotensin II type 1 (AT(1)) receptor: AT(1A) and AT(1B). It is unclear which receptor subtype mediates contraction in response to angiotensin II in various arteries. We tested the hypothesis that the AT(1B) receptor is the predominant receptor that mediates contraction in the abdominal aorta in response to angiotensin II. Isometric tension responses to angiotensin II were determined in abdominal aortic rings obtained from male wild-type and AT(1B) receptor knockout mice. The rings were suspended in an organ bath of a wire myograph and contractions to angiotensin II and other vasoconstrictors were determined. Angiotensin II contracted aortic segments from wild-type mice; however, this response was virtually absent in rings obtained from AT(1B) receptor knockout mice. Contractions in response to K(+) and U46619 (thromboxane A(2) mimetic) were not different between rings obtained from wild-type and AT(1B) receptor knockout mice. Reduced angiotensin...

Comprehensive Physiology, 2013

Historically, tools to assess renal function have been developed to investigate the physiology of... more Historically, tools to assess renal function have been developed to investigate the physiology of the kidney in an experimental setting, and certain of these techniques have utility in evaluating renal function in the clinical setting. The following work will survey a spectrum of these tools, their applications and limitations in four general sections. The first is clearance, including evaluation of exogenous and endogenous markers for determining glomerular filtration rate, the adaptation of estimated glomerular filtration rate in the clinical arena, and additional clearance techniques to assess various other parameters of renal function. The second section deals with in vivo and in vitro approaches to the study of the renal microvasculature. This section surveys a number of experimental techniques including corticotomy, the hydronephrotic kidney, vascular casting, intravital charge coupled device videomicroscopy, multiphoton fluorescent microscopy, synchrotron-based angiography, laser speckle contrast imaging, isolated renal microvessels, and the perfused juxtamedullary nephron microvasculature. The third section addresses in vivo and in vitro approaches to the study of renal blood flow. These include ultrasonic flowmetry, laser-Doppler flowmetry, magnetic resonance imaging (MRI), phase contrast MRI, cine phase contrast MRI, dynamic contrast-enhanced MRI, blood oxygen level dependent MRI, arterial spin labeling MRI, x-ray computed tomography, and positron emission tomography. The final section addresses the methodologies of metabolic balance studies. These are described for humans, large experimental animals as well as for rodents. Overall, the various in vitro and in vivo topics and applications to evaluate renal function should provide a guide for the investigator or physician to understand and to implement the techniques in the laboratory or clinic setting.

American Journal of Physiology - Renal Physiology, 2001

The intrarenal expression of angiotensin II (ANG II) type 1 (AT(1)) receptors and angiotensin-con... more The intrarenal expression of angiotensin II (ANG II) type 1 (AT(1)) receptors and angiotensin-converting enzyme (ACE) was determined in ANG II-induced hypertensive rats (80 ng/min; 2 wk). Systolic blood pressure averaged 184 +/- 3 and 125 +/- 1 mmHg in ANG II-infused compared with Sham rats on day 12. Total kidney AT(1) receptor protein levels were not altered significantly. AT(1) receptor binding mapped by quantitative in vitro autoradiography was significantly decreased in glomeruli (172 +/- 25 vs. 275 +/- 34 disintegrations. min(-1). mm(-2)) and the inner stripe of the outer medulla (121 +/- 17 vs. 178 +/- 19 disintegrations. min(-1). mm(-2)), but not proximal convoluted tubules (48 +/- 9 vs. 58 +/- 6 disintegrations. min(-1). mm(-2)) of ANG II-infused compared with Sham rats. Proximal tubule ACE binding was significantly augmented (132 +/- 4 vs. 97 +/- 3 disintegrations. min(-1). mm(-2)) in ANG II-infused rats. In summary, during ANG II-induced hypertension, glomeruli and inner stripe of the outer medulla have reduced AT(1) receptor binding. Proximal convoluted tubules exhibit maintained AT(1) receptor density and increased ACE binding, which together with the elevated ANG II levels suggest that ANG II exerts a sustained influence on tubular reabsorption and consequently contributes to the development and maintenance of ANG II-dependent hypertension.

International journal of physiology, pathophysiology and pharmacology, 2012

Atrial natriuretic peptide (ANP) exerts an inhibitory effect on juxtaglomerular (JG) renin synthe... more Atrial natriuretic peptide (ANP) exerts an inhibitory effect on juxtaglomerular (JG) renin synthesis and release by activating guanylyl cyclase/ natriuretic peptide receptor-A (GC-A/NPRA). Renin has also been localized in connecting tubule cells; however, the effect of ANP/NPRA signaling on tubular renin has not been determined. In the present study, we determined the role of NPRA in regulating both JG and tubular renin using Npr1 (coding for NPRA) gene-disrupted mice, which exhibit a hypertensive phenotype. Renin-positive immunoreactivity in Npr1(-/-) homozygous null mutant mice was significantly reduced compared with Npr1(+/+) wild-type mice (23% vs 69% renin-positive glomeruli). However, after chronic diuretic treatment, Npr1(-/-) mice showed an increment of JG renin immunoreactivity compared with Npr1(+/+) mice (70% vs 81% renin-positive glomeruli). There were no significant differences in the distal tubule renin between Npr1(+/+) and Npr1(-/-) mice. However, after diuretic trea...

American Journal of Hypertension, 2000

Because of the importance of the renin-angiotensin system in the pathophysiology of hypertension ... more Because of the importance of the renin-angiotensin system in the pathophysiology of hypertension and in mediating associated alterations in renal function, angiotensin II (Ang II) AT 1 receptor blockers provide a direct means of protecting against influences of excessive Ang II levels. The kidney is an important site of action of Ang II AT 1 receptor blockers because intrarenal Ang II not only vasoconstricts the renal vasculature but also reduces sodium excretion and suppresses the pressure natriuresis relationship. Even in normal conditions, intrarenal Ang II content is greater than can be explained on the basis of circulating Ang II and is compartmentalized with proximal tubule concentrations of Ang I and Ang II being several times higher than plasma concentrations.

Kidney International, 2002

Background-In rats maintained on a high salt diet (H/S) to suppress basal renal angiotensinogen l... more Background-In rats maintained on a high salt diet (H/S) to suppress basal renal angiotensinogen levels, angiotensin II (Ang II) infusion for 13 days increased renal angiotensinogen mRNA and protein, thus providing a mechanism for further augmentation of intrarenal Ang II levels. The present study tested the hypothesis that enhanced intrarenal angiotensinogen formation during Ang II infusion is reflected by secretion into the tubular fluid leading to increased urinary excretion of angiotensinogen (U AGT ).

Journal of the Renin-Angiotensin-Aldosterone System, 2001

Journal of the American Society of Nephrology, 2007

Cross-talk between G protein-coupled receptors (GPCR) is known to occur at multiple levels, inclu... more Cross-talk between G protein-coupled receptors (GPCR) is known to occur at multiple levels, including receptor heterodimerization and intracellular signaling. This study tested the hypothesis that GPCR cross-talk occurs at the transcriptional level. It was demonstrated that the bradykinin B2 receptor gene (BdkrB2) is a direct transcriptional target of the angiotensin II (AngII) type 1 receptor (AT(1)R) in collecting duct cells. AngII induced BdkrB2 mRNA expression in mouse inner medullary collecting duct cells, and this effect was abrogated by AT(1)R blockade; in contrast, AT(2)R blockade was ineffective. Actinomycin D, an inhibitor of gene transcription, abrogated AngII-stimulated BdkrB2 expression. In addition, AngII produced dosage- and time-dependent increases in B2 receptor protein levels (2.9 +/- 0.4 fold; P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). AngII stimulated phosphorylation of cAMP response element binding protein (CREB) on Ser-133 and assembly of p-CREB on the BdkrB2 promoter in vivo. Moreover, AngII induced hyperacetylation of BdkrB2 promoter-associated H4 histones, a chromatin modification that is associated with gene activation. Mutations of the CRE abrogated AngII-induced activation of the BdkrB2 promoter. AngII-treated inner medullary collecting duct cells exhibited augmented intracellular calcium signaling in response to bradykinin, confirming the functional relevance of AT(1)-B2 receptor signaling. Finally, studies that were conducted in angiotensin type 1 receptor (Agtr1)-null mice revealed that BdkrB2 mRNA levels were significantly lower in the renal medulla of Agtr1(A)(-/-) and Agtr1(A/B)(-/-) than in Agtr1(+/+) and Agtr1(B)(-/-) mice. It is concluded that BdkrB2 is a downstream target of the AT(1)R-CREB signaling pathway. Transcriptional regulation represents a novel form of cross-talk between GPCR that link the renin-angiotensin and kallikrein-kinin systems.

The Clinical Investigator, 1994

ABSTRACT

Journal of Histochemistry and Cytochemistry, 2007

S U M M A R Y The present study was performed to determine the influence of absence of angiotensi... more S U M M A R Y The present study was performed to determine the influence of absence of angiotensin type 1A (AT 1A ) and/or AT 1B receptor feedback regulation of kidney neuronal nitric oxide synthase (nNOS) and renin protein expression. Kidneys were harvested from wildtype (WT), AT 1A 2/2 , AT 1B 2/2 , and AT 1A 2/2 AT 1B 2/2 mice and immunostained for nNOS and renin protein localization. AT 1A 2/2 and AT 1A 2/2 AT 1B 2/2 kidneys demonstrated an increase in the percentage of glomeruli with nNOS-positive afferent and interlobular arterioles compared with WT mice. Density of vascular nNOS immunostaining was 20-fold higher in kidneys of AT 1A 2/2 and AT 1A 2/2

Journal of Cardiovascular Pharmacology, 1990

Experiments were performed on conscious rats to (a) compare the responsiveness of the renal and h... more Experiments were performed on conscious rats to (a) compare the responsiveness of the renal and hindquarter vascular beds to infusions of exogenous arginine vasopressin (AVP), and (b) determine whether either bed demonstrates V2-vasopressinergic vasodilation when the vasoconstrictor properties of AVP are blocked. Rats were chronically instrumented with pulsed Doppler flow probes on either the left renal artery or the distal abdominal aorta as well as with femoral arterial and venous catheters. One series of experiments examined the vascular responses of these two beds to exogenous AVP infused intravenously (i.v.) at 0.2, 2.0, or 5.0 ng/min. The lowest infusion rate was associated with no detectable changes in mean arterial blood pressure (MAP), heart rate (HR), renal or hindquarter blood flow (RBF or HQBF), or vascular resistance in these beds. In contrast, the higher infusion rates caused a marked increase in MAP, a decrease in HR, and a reduction in HQBF; RBF was unaffected, however. A second series of experiments tested for the presence of a V2-vasodilatory influence during infusion of AVP at 5 ng/min by selectively blocking V1-vasopressinergic receptors or both V1- and V2-receptor types. Little evidence for V2-mediated vasodilation was found in either vascular bed, however. We conclude that although the renal vasculature appears relatively insensitive to exogenous AVP, this insensitivity probably is not due to vasodilation mediated by activation of V2-receptors.