RESUMEN
We examined whether deficits in glomerular capillary surface area associated with a congenital nephron deficit could be corrected by glomerular hypertrophy. Using unbiased stereological techniques, we examined the time course and mode of glomerular hypertrophy in mice lacking one allele for glial cell line-derived neurotrophic factor (GDNF). These GDNF heterozygous (Het) mice are born with approximately 30% less nephrons than wild-type (WT) littermates. An additional group of GDNF Het mice received the angiotensin type 1 (AT1)-receptor antagonist candesartan (Cand; 10 mg x kg(-1) x day(-1)) from 5 wk of age to determine the role of AT1 receptors in the compensatory hypertrophy. At 10 wk of age, the total volume of renal corpuscles, glomerular capillary surface area, and length of glomerular capillaries in the kidneys of GDNF Het mice were all markedly (approximately 45%) less than that of WT mice (P < 0.001). However, by 30 wk, and persisting at 60 wk of age, GDNF Het and WT mice did not significantly differ in any of these parameters. Furthermore, conscious 24-h mean arterial pressure (MAP) did not differ between GDNF Het and WT mice at any time point. MAP of GDNF Het-Cand mice was 20-30 mmHg less than that of GDNF Het-vehicle mice at all three ages, but Cand treatment did not significantly alter glomerular capillary dimensions. In conclusion, we have demonstrated that the deficit in glomerular capillary surface area associated with a congenital nephron deficit can be corrected for in adulthood by an increase in the total length of glomerular capillaries. This process does not require AT1 receptor activation.
Asunto(s)
Angiotensina II/metabolismo , Glomérulos Renales/anomalías , Receptor de Angiotensina Tipo 1/metabolismo , Bloqueadores del Receptor Tipo 1 de Angiotensina II , Animales , Bencimidazoles , Compuestos de Bifenilo , Presión Sanguínea , Peso Corporal , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca , Heterocigoto , Hipertrofia/patología , Glomérulos Renales/irrigación sanguínea , Glomérulos Renales/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Tamaño de los Órganos , TetrazolesRESUMEN
OBJECTIVE: To determine whether the responses of total peripheral resistance and arterial pressure to vasoconstrictor agents are amplified as renovascular hypertension develops in dogs. METHODS: After baseline measurements, the effects of renal artery stenosis (1K, 1C hypertension) were studied in groups of untreated and enalapril-treated dogs early (1-3 weeks) and later (4-6 weeks) as the hypertension developed. Both resting and open-loop haemodynamic measurements were made and the effects of acute intravenous infusions of vasopressin (0.25, 0.5 and 1.25 ng/kg per min) and phenylephrine (0.125, 0.25 and 0.50 microg/kg per min on arterial pressure, cardiac output and calculated total peripheral resistance responses were measured. RESULTS: Renal artery stenosis induced an increase in arterial blood pressure in both groups of dogs, with similar changes in haemodynamics also observed in open-loop conditions. The slopes of arterial pressure and peripheral resistance responses to vasopressin and phenylephrine were not significantly changed in early or late hypertension, in either the untreated or enalapril-treated groups. CONCLUSIONS: Hypertension from renal artery stenosis in dogs was due to nonautonomic, nonangiotensin II mechanisms. There was no evidence of vascular amplification of the effects of vasoconstrictor agents, indicating that this did not play a role in the development of hypertension.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Hipertensión Renovascular/fisiopatología , Resistencia Vascular/efectos de los fármacos , Vasoconstrictores/farmacología , Animales , Arginina Vasopresina/farmacología , Captopril/farmacología , Modelos Animales de Enfermedad , Perros , Enalapril , Bloqueadores Ganglionares/farmacología , Hipertensión Renovascular/tratamiento farmacológico , Masculino , Tartrato de Pentolinio/farmacología , Fenilefrina/farmacologíaRESUMEN
OBJECTIVE: To determine the effects of chronic denervation on renal vascular structure and function in young adult spontaneously hypertensive rats (SHRs). DESIGN: Unilateral renal denervation (SHRUDx) or sham-operation (SHRS) was performed in SHRs at 6 weeks of age. At 10 weeks, rats were allocated to one of three procedures designed to examine renal vascular structure and function. A further group underwent bilateral renal denervation. METHODS: In SHRUDx or SHRS groups, either the kidneys were perfusion-fixed for stereological estimates of artery wall and lumen dimensions or for vascular casting to determine arteriole lumen diameters, or the rats were anaesthetized for estimation of glomerular capillary pressure. RESULTS: Chronic unilateral renal denervation had no significant effect on the development of hypertension between 6 and 10 weeks of age, as previously reported, but resulted in luminal narrowing of the interlobular artery (denervated group 52 +/- 2 mum, sham-operated group 64 +/- 1 mum; P < 0.01 for interaction between strain and treatment), without alterations in interlobular or arcuate artery wall dimensions. There were no significant effects on either afferent or efferent arteriole lumen diameters. Estimated glomerular capillary pressure was significantly lower in the denervated kidneys of SHRUDx (47 +/- 1 mmHg) compared with kidneys of the SHRS (50 +/- 1 mmHg; P < 0.04). Mean arterial pressure was approximately 12 mmHg lower in the bilaterally denervated SHRs than in the sham-operated SHRs. CONCLUSIONS: Although bilateral denervation attenuated the development of hypertension in SHRs, unilateral denervation did not, indicating that one neurally intact kidney was sufficient to drive the normal development of SHR hypertension, but only with apparent prohypertensive compensatory changes in the denervated kidney.
Asunto(s)
Hipertensión Renal/patología , Hipertensión Renal/fisiopatología , Riñón/inervación , Simpatectomía , Sistema Nervioso Simpático/fisiología , Animales , Arteriolas/fisiología , Presión Sanguínea , Enfermedad Crónica , Estado de Conciencia , Molde por Corrosión , Riñón/irrigación sanguínea , Riñón/fisiología , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Circulación Renal/fisiologíaRESUMEN
BACKGROUND: Genetic noise between outbred animals can potentially be a major confounder in the use of microarray technology for gene expression profiling. The study of paired organs from the same animal offers an alternative approach (e.g., for studies of the kidney in experimental hypertension). The present study was undertaken to determine the level of genetic noise between outbred adult Sprague-Dawley (SD) rats, and to determine the effects of unilateral nephrectomy on changes in gene expression as a basis for the design of microarray studies in experimental hypertension. METHODS: Male SD rats (approximately 130 g) were acclimatized before measurement of tail-cuff systolic blood pressure (SBP) for 6 control days and 4 days of saline treatment. Left kidney nephrectomy was performed, and the tissue snap-frozen in liquid nitrogen for subsequent RNA extraction. Two weeks later, SBP was measured over 4 control and 8 saline treatment days, and the remaining right kidney removed and frozen. Total RNA purification, preparation of cRNA, hybridization, and scanning of the Rat U34A Affymetrix arrays were performed, and data analyzed using MAS5 software Affymetrix Suite (v5), Bioconductor, as well as statistical methods motivated by relevant simulations. RESULTS: Gene expression profiles in the left control kidney were extremely consistent across animals. The expression profiles of pairs of kidneys from the same animal were, however, more similar than those of kidneys from different animals. Nephrectomy had little effect on the gene expression profiles in the time frame examined. CONCLUSION: Despite the outbred nature of the rats used in this study, they are useful for gene expression profiling comparisons. The use of paired organs from an individual animal ensures even further genetic identity, allowing determination of genes modified by the treatment of interest.
Asunto(s)
Hipertensión/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Animales , ADN Complementario/genética , Interpretación Estadística de Datos , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica/métodos , Perfilación de la Expresión Génica/estadística & datos numéricos , Hipertensión/etiología , Riñón/metabolismo , Masculino , Nefrectomía , Análisis de Secuencia por Matrices de Oligonucleótidos/estadística & datos numéricos , Ratas , Ratas Sprague-DawleyRESUMEN
1. Medullary blood flow (MBF) is important in the long-term control of arterial pressure. However, it is unclear which vascular elements regulate MBF. 2. Exogenous endothelin (ET)-1 decreases cortical more than medullary blood flow. We hypothesized that ET-1 would therefore constrict afferent (AA) and efferent arterioles (EA) of juxtamedullary glomeruli less than those of cortical glomeruli. 3. Mean arterial pressure, renal blood flow and cortical (CBF) and medullary (MBF) blood flow, via laser-Doppler flowmetry, were measured before and after intrarenal ET-1 (2 ng/kg per min; n = 6) or vehicle (n = 6) in anaesthetized rabbits. Kidneys were perfusion fixed, vascular casts formed, lumen diameters measured via scanning electron microscopy and relative resistance calculated. 4. Mean arterial pressure was not significantly affected by ET-1 infusion. Cortical glomerular arteriole lumen diameters were significantly reduced in the ET-1-infused group (AA approximately 30%, EA approximately 18%; PA < 0.01), compatible with the decrease in CBF (42 +/- 3%; PGT < 0.01). Juxtamedullary arteriole lumen diameters were also significantly reduced in the ET-1-infused group (AA approximately 34%, EA approximately 21%; PA < 0.01); however, MBF did not decrease. 5. In conclusion, our data suggest that juxtamedullary arterioles are not of primary importance in the regulation of MBF because, despite reductions in juxtamedullary arteriole diameters in response to ET-1, MBF was not decreased.
Asunto(s)
Endotelina-1/farmacología , Circulación Renal/efectos de los fármacos , Animales , Arteriolas/efectos de los fármacos , Arteriolas/fisiología , Corteza Renal/irrigación sanguínea , Corteza Renal/efectos de los fármacos , Corteza Renal/fisiología , Médula Renal/irrigación sanguínea , Médula Renal/efectos de los fármacos , Médula Renal/fisiología , Masculino , Conejos , Flujo Sanguíneo Regional/fisiología , Circulación Renal/fisiologíaRESUMEN
The renal nerves constrict the renal vasculature, causing decreases in renal blood flow (RBF) and glomerular filtration rate (GFR). Whether renal haemodynamics are influenced by changes in renal nerve activity within the physiological range is a matter of debate. We have identified two morphologically distinct populations of nerves within the kidney, which are differentially distributed to the renal afferent and efferent arterioles. Type I nerves almost exclusively innervate the afferent arteriole whereas type II nerves are distributed equally on the afferent and efferent arterioles. We have also demonstrated that type II nerves are immunoreactive for neuropeptide Y, whereas type I nerves are not. This led us to hypothesize that, in the kidney, distinct populations of nerves innervate specific effector tissues and that these nerves may be selectively activated, setting the basis for the differential neural control of GFR. In physiological studies, we demonstrated that differential changes in glomerular capillary pressure occurred in response to graded reflex activation of the renal nerves, compatible with our hypothesis. Thus, sympathetic outflow may be capable of selectively increasing or decreasing glomerular capillary pressure and, hence, GFR by differentially activating separate populations of renal nerves. This has important implications for our understanding of the neural control of body fluid balance in health and disease.
Asunto(s)
Tasa de Filtración Glomerular/fisiología , Hemofiltración , Glomérulos Renales/inervación , Glomérulos Renales/fisiología , Neuronas/fisiología , Animales , HumanosRESUMEN
We have shown previously that a moderate reflex increase in renal sympathetic nerve activity (RSNA) elevated glomerular capillary pressure, whereas a more severe increase in RSNA decreased glomerular capillary pressure. This suggested that the nerves innervating the glomerular afferent and efferent arterioles could be selectively activated, allowing differential control of glomerular capillary pressure. A caveat to this conclusion was that intrarenal actions of neurally stimulated ANG II might have contributed to the increase in postglomerular resistance. This has now been investigated. Anesthetized rabbits were prepared for renal micropuncture and RSNA recording. One group (ANG II clamp) received an infusion of an angiotensin-converting enzyme inhibitor (enalaprilat, 2 mg/kg bolus plus 2 mg.kg(-1).h(-1)) plus ANG II ( approximately 20 ng.kg(-1).min(-1)), the other vehicle. Measurements were made before (room air) and during 14% O(2). Renal blood flow decreased less during ANG II clamp compared with vehicle [9 +/- 1% vs. 20 +/- 4%, interaction term (P(GT)) < 0.05], despite a similar increase in RSNA in response to 14% O(2) in the two groups. Arterial pressure and glomerular filtration rate were unaffected by 14% O(2) in both groups. Glomerular capillary pressure increased from 33 +/- 1 to 37 +/- 1 mmHg during ANG II clamp and from 33 +/- 2 to 35 +/- 1 mmHg in the vehicle group before and during 14% O(2), respectively (P(GT) < 0.05). During ANG II clamp, postglomerular vascular resistance was still increased in response to RSNA during 14% O(2), demonstrating that the action of the renal nerves on the postglomerular vasculature was independent of the renin-angiotensin system. This further supports our hypothesis that increases in RSNA can selectively control pre- and postglomerular vascular resistance and therefore glomerular ultrafiltration.
Asunto(s)
Angiotensina II/farmacología , Riñón/inervación , Circulación Renal/fisiología , Sistema Nervioso Simpático/fisiología , Resistencia Vascular/fisiología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Enalaprilato/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Hipoxia/fisiopatología , Riñón/efectos de los fármacos , Glomérulos Renales/irrigación sanguínea , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/fisiología , Masculino , Oxígeno/farmacología , Conejos , Reflejo/efectos de los fármacos , Reflejo/fisiología , Circulación Renal/efectos de los fármacos , Sistema Nervioso Simpático/efectos de los fármacos , Resistencia Vascular/efectos de los fármacosRESUMEN
This study investigated the effects of graded reflex increases in renal sympathetic nerve activity (RSNA) on renal preglomerular and postglomerular vascular resistances. With the use of hypoxia to reflexly elicit increases in RSNA without affecting mean arterial pressure, renal function and stop-flow pressures were measured in three groups of rabbits before and after exposure to room air and moderate (14% O2) or severe (10% O2) hypoxia. Moderate and severe hypoxia increased RSNA, primarily by increasing the amplitude of the sympathetic bursts rather than their frequency. RSNA amplitude increased by 20 +/- 6% (P < 0.05) and 60 +/- 16% (P < 0.05), respectively. Moderate hypoxia decreased estimated renal blood flow (ERBF; 26 +/- 7%; P = 0.07), whereas estimated glomerular capillary pressure (32 +/- 1 versus 34 +/- 1 mmHg; P < 0.05) and filtration fraction (FF; P < 0.01) increased. In response to moderate hypoxia, calculated preglomerular (approximately 20%) and postglomerular (approximately 70%) resistance both increased, but only the increase in postglomerular resistance was significant (P < 0.05). In contrast, severe hypoxia decreased ERBF (56 +/- 8%; P < 0.01), GFR (55 +/- 9%; P < 0.001), and glomerular capillary pressure (32 +/- 1 versus 29 +/- 1 mmHg; P < 0.001), with no change in FF, reflecting similar preglomerular (approximately 240%; P < 0.05) and postglomerular ( approximately 250%; P < 0.05) contributions to the vasoconstriction and a decrease in calculated K(f) (P < 0.05). These results provide evidence that reflexly induced increases in RSNA amplitude may differentially control preglomerular and postglomerular vascular resistances.