Impaired EphA4 signaling leads to congenital hydronephrosis, renal injury, and hypertension

2013 ◽  
Vol 305 (1) ◽  
pp. F71-F79 ◽  
Author(s):  
Johan Sällström ◽  
Christiane Peuckert ◽  
Xiang Gao ◽  
Erik Larsson ◽  
Anders Nilsson ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Impairment ◽  
Glomerular Filtration ◽  
Plasma Flow ◽  
Fluorescent Protein ◽  
Renal Plasma Flow ◽  
Blood Pressure Level ◽  
Congenital Hydronephrosis ◽  
Experimental Hydronephrosis ◽  
Renal Injuries

Experimental hydronephrosis induced by partial ureteral obstruction at 3 wk of age causes hypertension and renal impairment in adult rats and mice. Signaling by Ephrin receptors (Eph) and their ligands (ephrins) importantly regulates embryonic development. Genetically modified mice, where the cytoplasmic domain of the EphA4 receptor has been substituted by enhanced green fluorescent protein ( EphA4 gf/gf), develop spontaneous hydronephrosis and provide a model for further studies of the disorder. The present study aimed to determine if animals with congenital hydronephrosis develop hypertension and renal injuries, similar to that of experimental hydronephrosis. Ultrasound and Doppler techniques were used to visualize renal impairment in the adult mice. Telemetric blood pressure measurements were performed in EphA4 gf/gf mice and littermate controls ( EphA4 +/+) during normal (0.7% NaCl)- and high (4% NaCl)-sodium conditions. Renal excretion, renal plasma flow, and glomerular filtration were studied, and histology and morphology of the kidneys and ureters were performed. EphA4 gf/gf mice developed variable degrees of hydronephrosis that correlated with their blood pressure level. In contrast to EphA4 +/+, the EphA4 gf/gf mice displayed salt-sensitive hypertension, reduced urine concentrating ability, reduced renal plasma flow, and lower glomerular filtration rate. Kidneys from EphA4 gf/gf mice showed increased renal injuries, as evidenced by fibrosis, inflammation, and glomerular and tubular changes. In conclusion, congenital hydronephrosis causes hypertension and renal damage, similar to that observed in experimentally induced hydronephrosis. This study further reinforces the supposed causal link between hydronephrosis and later development of hypertension in humans.

Influence of nifedipine on cyclosporin A nephrotoxicity after unilateral nephrectomy in the spontaneously hypertensive rat

1991 ◽  
Vol 81 (2) ◽  
pp. 271-279 ◽  
Author(s):  
P. G. McNally ◽  
F. Baker ◽  
N. Mistry ◽  
J. Walls ◽  
J. Feehally
Keyword(s):  
Body Weight ◽  
Glomerular Filtration Rate ◽  
Renal Impairment ◽  
Cyclosporin A ◽  
Glomerular Filtration ◽  
Plasma Flow ◽  
Filtration Rate ◽  
Renal Denervation ◽  
Renal Plasma Flow ◽  
Spontaneously Hypertensive

1. Nifedipine ameliorates cyclosporin A-induced renal impairment in surgically intact (two-kidney) rats. This study investigates the effect of nifedipine on cyclosporin A nephrotoxicity in spontaneously hypertensive rats after either uninephrectomy or uninephrectomy with contralateral renal denervation. 2. Fourteen days after uninephrectomy pair-fed rats were injected for 14 days with cyclosporin A (25 mg/kg body weight) via the subcutaneous route and with nifedipine (0.1 mg/kg body weight) via the intraperitoneal route. Renal and systemic haemodynamics were measured in conscious unrestrained rats. 3. Whole-blood levels of cyclosporin A did not differ between groups (overall 352 ± 22 ng/ml, means ± sem). After uninephrectomy, cyclosporin A decreased the glomerular filtration rate (olive oil versus cyclosporin A: 0.96 ± 0.04 versus 0.70 ± 0.06 ml min−1 100 g body weight, P < 0.02) and effective renal plasma flow (1.94 ± 0.10 versus 1.38 ± 0.13, P < 0.01), and increased renal vascular resistance {(20.2 ± 1.8) × 104 versus (31.6 ± 3.3) × 104 kPa l−1 s [(20.2 ± 1.8) × 103 versus (31.6 ± 3.3) × 103 dyn s cm−5], P < 0.02} and mean arterial pressure (146.7 ± 6.7 versus 167.3 ± 2.9 mmHg, P < 0.05). Neither renal denervation nor nifedipine prevented the reduction in glomerular filtration rate or effective renal plasma flow induced by cyclosporin A. 4. This study infers that the sympathetic nervous system does not play an active role in cyclosporin A nephrotoxicity and demonstrates that the concomitant administration of nifedipine to rats with reduced renal mass does not ameliorate cyclosporin A-induced renal impairment.

Differential effect of T-type voltage-gated Ca2+ channel disruption on renal plasma flow and glomerular filtration rate in vivo

2014 ◽  
Vol 307 (4) ◽  
pp. F445-F452 ◽  
Author(s):  
Anne D. Thuesen ◽  
Henrik Andersen ◽  
Majken Cardel ◽  
Anja Toft ◽  
Steen Walter ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Blood Flow ◽  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Plasma Flow ◽  
Filtration Rate ◽  
Renal Plasma Flow ◽  
Voltage Gated

Voltage-gated Ca2+ (Cav) channels play an essential role in the regulation of renal blood flow and glomerular filtration rate (GFR). Because T-type Cav channels are differentially expressed in pre- and postglomerular vessels, it was hypothesized that they impact renal blood flow and GFR differentially. The question was addressed with the use of two T-type Cav knockout (Cav3.1−/− and Cav3.2−/−) mouse strains. Continuous recordings of blood pressure and heart rate, para-aminohippurate clearance (renal plasma flow), and inulin clearance (GFR) were performed in conscious, chronically catheterized, wild-type (WT) and Cav3.1−/− and Cav3.2−/− mice. The contractility of afferent and efferent arterioles was determined in isolated perfused blood vessels. Efferent arterioles from Cav3.2−/− mice constricted significantly more in response to a depolarization compared with WT mice. GFR was increased in Cav3.2−/− mice with no significant changes in renal plasma flow, heart rate, and blood pressure. Cav3.1−/− mice had a higher renal plasma flow compared with WT mice, whereas GFR was indistinguishable from WT mice. No difference in the concentration response to K+ was observed in isolated afferent and efferent arterioles from Cav3.1−/− mice compared with WT mice. Heart rate was significantly lower in Cav3.1−/− mice compared with WT mice with no difference in blood pressure. T-type antagonists significantly inhibited the constriction of human intrarenal arteries in response to a small depolarization. In conclusion, Cav3.2 channels support dilatation of efferent arterioles and affect GFR, whereas Cav3.1 channels in vivo contribute to renal vascular resistance. It is suggested that endothelial and nerve localization of Cav3.2 and Cav3.1, respectively, may account for the observed effects.

Glomerular filtration and renal plasma flow during hyperthermia

1960 ◽  
Vol 198 (5) ◽  
pp. 1044-1048 ◽  
Author(s):  
G. S. Kanter
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Glomerular Filtration ◽  
Plasma Volume ◽  
Plasma Flow ◽  
Filtration Rate ◽  
Renal Plasma Flow ◽  
Control Value ◽  
Acid Clearance ◽  
Anesthetized Dogs

The purpose of this study was to investigate the factors that determine the direction and magnitude of the alteration in GFR (glomerular filtration rate) and RPF (renal plasma flow) in hyperthermia. The investigation was conducted on anesthetized dogs. Creatinine clearance was used as a measure of GFR and para-aminohippuric acid clearance was used as a measure of RPF. The GFR in 12 mildly dehydrated dogs went from a control value of 68.4 ± 4.5 ml/min. at RT (rectal temperature) of 38.9°C to a GFR of 25.1 ± 8.5 ml/min. at a RT of 42.1°C at the end of 5 hours of exposure to heat. Final dehydration averaged –2.0% body weight. The fall in GFR and RPF was not due to dehydration for in a group of six hydrated dogs (+4% body wt. at end) similar results were obtained. No decrease in GFR or RPF occurred in either hydrated or dehydrated dogs until severe hyperthermia (> 41.2°C) was present. Though there was a decline in blood pressure towards the end of each experiment, in both groups, the decrease in GFR and RPF preceded any marked fall in pressure. Both groups showed an increase in hematocrit and a decrease in plasma volume (measured by T-1824 dilution) which became marked at the end of 5 hours of exposure to heat. The decrease in GFR and RPF appears directly related to the hyperthermia for upon rapid cooling GFR and RPF increases towards normal in spite of the persisting decreased blood pressure and plasma volume and increased hematocrit.

Inhibition of platelet-activating factor induced renal hemodynamic and tubular dysfunctions with L-655,240, a new thromboxane–prostaglandin endoperoxide antagonist

1989 ◽  
Vol 67 (4) ◽  
pp. 304-308 ◽  
Author(s):  
R. L. Hébert ◽  
P. Sirois ◽  
G. E. Plante
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Glomerular Filtration ◽  
Plasma Flow ◽  
Filtration Rate ◽  
Renal Plasma Flow ◽  
Platelet Activating Factor ◽  
Urinary Sodium ◽  
Dependent Manner ◽  
Prostaglandin Endoperoxide

The continuous infusion or bolus injection of the platelet-activating factor (PAF) is associated with profound hypotension, marked reductions of renal plasma flow, glomerular filtration, and urinary sodium excretion. All these effects are inhibited by blocking PAF receptors. To examine further the potential mediators of PAF on renal function, we utilized L-655,240 (6 mg/kg, intravenously), a thromboxane–prostaglandin endoperoxide antagonist, to study the systemic and renal response to PAF (0.8 μg/kg, intravenously) in the anesthetized dog, using clearance methodology. PAF decreased blood pressure from 115 ± 7 to 54 ± 4 mmHg (1 mmHg = 133.3 Pa), renal plasma flow from 105 ± 6 to 74 ± 56 mL/min, and glomerular filtration from 43 ± 3 to 32 ± 1 mL/min. PAF also reduced urine volume from 1.1 ± 0.2 to 0.4 ± 0.1 mL/min, and urinary sodium from 158 ± 7 to 86 ± 7 μequiv./min. L-655,240 alone had no significant effect on blood pressure, renal plasma flow, and filtration rate, at any dose. However, the 6-mg/kg dose resulted in a slight elevation of diuresis, from 1.1 ± 0.2 to 1.9 ± 0.1 mL/min, and urinary sodium, from 134 ± 13 to 212 ± 19 μequiv./min. All doses of L-655,240 blocked the effect of PAF on blood pressure. However, the two lower doses of this antagonist (1 and 3 mg/kg) failed to prevent the PAF-induced fall of renal plasma flow and filtration rate, and attenuated the effect on urinary sodium in a dose-dependent manner. These results indicate that the renal vasoconstriction and antinatriuretic effects of PAF are probably mediated by thromboxane A2 and (or) prostaglandin endoperoxides in the dog. L-655,240 represents therefore a potent inhibitor of PAF-induced renal dysfunctions, and may be of significant interest to explore further the physiology and pathophysiology of PAF.Key words: platelet-activating factor, renal function, lipid mediators, thromboxane antagonist, shock.

Clinical Renal Function Testing by External Double Isotope Monitoring Technique

1971 ◽  
Vol 10 (01) ◽  
pp. 16-24
Author(s):  
J. Fog Pedersen ◽  
M. Fog Pedersen ◽  
Paul Madsen
Keyword(s):  
Renal Function ◽  
Glomerular Filtration Rate ◽  
Glomerular Filtration ◽  
Plasma Flow ◽  
Filtration Rate ◽  
Renal Plasma Flow ◽  
Correlation Coefficients ◽  
Feedback System ◽  
Effective Renal Plasma Flow ◽  
Advantages And Disadvantages

SummaryAn accurate catheter-free technique for clinical determination simultaneouslyof glomerular filtration rate and effective renal plasma flow by means of radioisotopes has been developed. The renal function is estimated by the amount of radioisotopes necessary to maintain a constant concentration in the patient’s blood. The infusion pumps are steered by a feedback system, the pumps being automatically turned on when the radiation measured over the patient’s head falls below a certain preset level and turned off when this level is again readied. 131I-iodopyracet was used for the estimation of effective renal plasma flow and125I-iothalamate estimation of the glomerular filtration rate. These clearances were compared to the conventional bladder clearances and good correlation was found between these two clearance methods (correlation coefficients 0.97 and.90 respectively). The advantages and disadvantages of this new clearance technique are discussed.

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