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N Gretz

Publications and source records attributed to N Gretz.

At least 73 records · Page 4Linked to original sources
PubMed1996

Function and expression of endothelin receptor subtypes in the kidneys of spontaneously hypertensive rats.

OBJECTIVE: The renal endothelin system has been implicated in the development and maintenance of hypertension in spontaneously hypertensive rats (SHR). However, little is known about the function and cellular distribution of endothelin receptor subtypes in the kidneys of SHR. METHODS: We analyzed the expression of endothelin receptor subtypes in the kidneys of 16-week-old SHR using Scatchard analysis, receptor autoradiography, Northern blot analysis and in situ hybridization. Wistar-Kyoto rats (WKY) served as controls. Furthermore, we investigated the effects of the mixed (A/B) endothelin receptor antagonist bosentan and the ETA receptor antagonist BQ 123 on mean arterial blood pressure (MAP), renal blood flow (RBF) and glomerular filtration rate (GFR) in conscious chronically instrumented rats. RESULTS: In SHR, we found by receptor autoradiography an overexpression of the endothelin A receptor (ETA) in the glomeruli (2.2 +/- 0.4-fold; P < 0.05) and smooth muscle cells of intrarenal arteries (1.9 +/- 0.2-fold; P < 0.05) compared to age-matched WKY. In addition, our study revealed a pronounced upregulation of endothelin B receptor (ETB) in the glomeruli of SHR (5.6 +/- 0.8-fold; P < 0.01). Blockade of endothelin receptors in SHR with bosentan (A and B receptor blockade) as well as with BQ 123 (A receptor blockade) led to a significant decrease in MAP (-18.6 +/- 2.1 and -19 +/- 1.3 mmHg, respectively; P < 0.05 in both cases) and a significant increase in RBF (+2.8 +/- 0.5 and +3.1 +/- 0.37 ml/min, respectively; P < 0.05 in both cases). The blockade of both ETA and ETB by bosentan had no further effect on MAP reduction or RBF increase in SHR compared to the ETA blockade by BQ 123. The ETA antagonist BQ 123 had no effect on GFR either in SHR or in WKY, whereas the combined blockade of ETA and ETB by bosentan significantly decreased GFR in SHR by about 50% but not in WKY. CONCLUSIONS: Our data demonstrated a correlation between the overexpression of vascular ETA receptors and the pronounced upregulation of glomerular ETB receptors in the kidneys of SHR and their impact on the regulation of renal blood flow, glomerular filtration rate and blood pressure in these animals.

Animals↗
PubMed1996

Autoregulation of renal blood flow and pressure-dependent renin release in autosomal dominant polycystic kidney disease of rats.

The Han:SPRD (PKD) rat is a new animal model of autosomal dominant polycystic kidney disease (ADPKD) which resembles many clinical and pathoanatomical features of human ADPKD. The aim of the present study was to analyse age-dependent changes in renal haemodynamics and renal renin secretion which could be of pathophysiological importance in the course of the disease. We investigated glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistance (RVR), plasma renin activity (PRA), the autoregulatory behaviour of RBF and the pressure-dependent plasma renin activity in conscious PKD rats compared with age-matched controls. Experiments were performed in conscious chronically instrumented PKD rats (age: 3 and 9 months) and their age-matched genetic controls. GFR in 3-(0.52 +/- 0.07 ml/min/100 g; n = 9) and 9-month-old (0.42 +/- 0.03 ml/min/100 g; n = 21) PKD rats were significantly lower (P < 0.05) than 3- (0.92 +/- 0.07 ml/min/100 g; n = 17) and 9-month-old (0.67 +/- 0.05 ml/min/100 g; n = 17) controls. Nine-month-old PKD revealed a significant (P < 0.005) resetting of the breakpoint of RBF autoregulation towards lower pressures (85.5 +/- 4.4 mmHg; n = 10) than either age-matched controls (102.8 +/- 2.5 mmHg; n = 11) or young PKD (107.5 +/- 4.4 mmHg; n = 6). The basal plasma renin activity was significantly (P < 0.05) lower in 3-month-old PKD than in old PKD and age-matched controls. A significant shift of threshold pressure for pressure-dependent renin release to lower pressures was observed in PKD rats. The observed improvement of autoregulatory reserve, at least in the low pressure range, could be of pathophysiological importance in delaying the progression of chronic renal failure in ADPKD. The suppression of the renin angiotensin system in young PKD could explain the fact that we did not observe hypertension in PKD rats, which is a major difference between this animal model and human ADPKD.

Aging↗
PubMed1995

The treatment of cystinosis with cysteamine and phosphocysteamine in the United Kingdom and Eire.

Fifty-nine patients with cystinosis were treated with cysteamine or phosphocysteamine in the United Kingdom up to May 1990. Treatment was started at a median age of 3.2 years (range 0.6-24.8 years) and continued for a median duration of 3.0 years (range 0.01-1.2 years). At the end of the study, 46 (78%) patients remained on treatment. One patient developed end-stage renal failure and 6 died. Efficacy was assessed in the 44 pre-transplant patients. The United Kingdom pre-transplant patients had significantly lower plasma creatinine concentrations at 6 and 8 years than a historical group of patients who did not receive cysteamine (P < 0.0001 and P < 0.0003, respectively). There was no significant difference between pretreatment and final post-treatment height standard deviation scores, suggesting maintenance of growth rate. The leucocyte cystine concentration was less than the accepted upper limit of the treatment range (1 nmol 1/2 cystine/mg protein) in only 21% of determinations. There was no significant difference between the mean pre-treatment and final values of leucocyte cystine concentration. The mean final doses of cysteamine (33 mg/kg per day) and phosphocysteamine (37 mg/kg per day base equivalent) were less than the mean dose (51 mg/kg per day) used in a United States multicentre trial. We conclude that cysteamine treatment was beneficial, but further improvements might be achieved by an improvement in monitoring of therapy.

Adolescent↗
PubMed1995

Gender-dependent disease severity in autosomal polycystic kidney disease of rats.

The impact of gender on the course of chronic renal failure in polycystic kidney disease (PKD) has been under discussion for years. Recently an animal model of autosomal dominant PKD in the rat became available allowing this topic to be studied. The aim of this study was to evaluate disease severity according to gender, and the occurrence of anticipation and/or genetic imprinting. Male and female affected PKD rats were crossed with respective Wistar-Ottawa-Karlsburg (WOK) rats. From this P generation 26 affected F1 hybrids were obtained, which were then backcrossed with WOK rats, resulting in 275 backcrosses (BC generation). In BC rats the affected males had a significantly higher kidney weight, worse histology and poorer renal function than the females. In the male, but not the female rats of the BC generation, transmission from an affected F1 mother resulted in significantly higher kidney weight, worse histology and poorer renal function than when the gene was inherited through an affected father. Since at the same time body and kidney weight were higher in the respective unaffected males, the previous effect in the affected rats might be due to a growth factor transferred by the mother's milk. The sex of the P generation had no such impact on these parameters. Thus our data provide no evidence for disease anticipation and genetic imprinting (in the classical sense) in the PKD rats, and the assumption of a gender-dependent disease expressivity is favored.

Animals↗
PubMed1995

Distribution of endothelin receptor subtypes in the rat kidney. Renal and haemodynamic effects of the mixed (A/B) endothelin receptor antagonist bosentan.

The paracrine renal endothelin system has been implicated in acute and chronic kidney diseases. However, there are only few data about the expression of endothelin receptor subtypes and their impact on renal function in the normal rat kidney. Therefore, we analyzed the age-dependent expression of endothelin receptors (endothelin receptor A and B) using Scatchard analysis, in vitro and in vivo receptor autoradiography. Furthermore, we investigated the effects of the mixed (A/B) endothelin receptor antagonist bosentan on haemodynamic and renal function in conscious chronically instrumented rats. The renal endothelin receptor A and endothelin receptor B expression is age-dependent. The relative amount of endothelin receptor A significantly decreased with age, whereas the endothelin receptor B significantly increased with age. Compared to the other renal structures, a high endothelin receptor density (endothelin receptor B >> endothelin receptor A) was seen in the renal tubules and even more in the glomeruli. Bosentan blocks both the pressor and depressor response of endothelin. Blocking of both endothelin receptor subtypes using bosentan without application of endothelin, on the other hand, did not alter blood pressure, heart rate, renal blood flow, water excretion or glomerular filtration rate, but significantly decreased sodium excretion.

Aging↗
PubMed1995

Significance of endothelin receptor subtypes in the kidneys of spontaneously hypertensive rats: renal and hemodynamic effects of endothelin receptor antagonists.

The renal endothelin (ET) system has been implicated in the maintenance of hypertension in spontaneously hypertensive rats (SHRs). However, little is known about the expression and cellular distribution of the ET receptor subtypes in the kidney of SHRs. We therefore analyzed the expression of ET receptor subtypes in the kidneys of 16-week-old SHRs. Wistar-Kyoto (WKY) rats served as controls. Furthermore, we investigate the effects of the ETA receptor antagonist BQ 123 and the mixed (ETA/ETB) receptor antagonist bosentan on mean arterial blood pressure (MAP), renal blood flow (RBF), and glomerular filtration rate (GFR) in conscious, chronically instrumented rats. In SHRs we found overexpression of the ETA in the glomeruli and smooth muscle cells of intrarenal arteries compared to age-matched WKY rats. Furthermore, our study revealed a pronounced upregulation of the ETB in the glomeruli of SHRs. Blockade of ETA and ETB receptors in SHR with bosentan as well as with BQ 123 led to a significant decrease in MAP and a significant increase in RBF, indicating that the ETA receptor plays a major role in the maintenance of high blood pressure and the regulation of RBF in SHRs. The blockade of both ETA and ETB receptors by bosentan has no further effect on MAP reduction or increase in RBF in SHRs compared to ETA blockade by BQ 123. In contrast, combined blockade of ETA and ETB receptors by bosentan significantly decreased GFR in SHRs, whereas no effect on GFR was observed in WKY rats, suggesting that the glomerular ETB overexpression in SHRs is of pathophysiologic relevance.

Animals↗
PubMed1995

Osmotically induced natriuresis and blood pressure response involves angiotensin AT1 receptors in the subfornical organ.

OBJECTIVE: In the present study we tested the hypothesis of whether the centrally induced natriuresis and blood pressure increase after intracerebroventricular injection of hypertonic saline involves the subfornical organ, as suggested by the occurrence of osmosensitive cells as well as a high concentration of angiotensin II receptors in this brain area. METHODS: All experiments were performed in conscious Wistar rats. A chronic cannula was inserted into the lateral brain ventricle for intracerebroventricular injection and a chronic indwelling intracranial guide cannula for microinjection was placed in the subfornical organ. In addition, the rats were provided with ureter catheters for urine collection. RESULTS: Intracerebroventricular injections of hypertonic saline (0.3 mol/l; n = 7) increased renal sodium excretion from 180.0 +/- 30.0 to 279.0 +/- 34.0 mol/l/60 min (P < 0.001) accompanied by an increase in mean arterial pressure of 8.3 +/- 1.2 mmHg (P < 0.01). No change in urinary volume was observed. After injection of the specific AT1 receptor antagonist, losartan, into the subfornical organ (5 micrograms/200 nl; n = 8) the natriuresis and blood pressure response to intracerebroventricular hypertonic saline was completely abolished. Control injections of losartan into areas adjacent to the subfornical organ had no effect on the responses to hypertonic saline. CONCLUSION: Our results suggest that the centrally induced natriuresis and blood pressure responses to hypertonic saline are mediated by an angiotensinergic mechanism involving the subfornical organ.

Animals↗
PubMed1994

Progression of chronic renal failure in a historical group of patients with nephropathic cystinosis. European Collaborative Study on Cystinosis.

In a historical group of 205 patients with infantile or adolescent cystinosis treated without cysteamine, the rate of deterioration of renal function was analysed retrospectively. Patient survival curves and renal survival data are presented. Longitudinal data of serum creatinine values (n = 3280) in 157 patients were plotted for each patient, smoothed by the method of the running medians and grouped into 12 serum creatinine classes. In every patient the age at the last smoothed serum creatinine value observed in each serum creatinine class was determined. These virtual age values were then summarized per serum creatinine class, expressed as median and centiles and plotted, thus describing the "natural" course of the disease. In 9 pairs of affected siblings the rate of progression showed a median difference of about 12 months. Our data describe the "natural" course of nephropathic cystinosis and can be used as a prognostic aid for recently detected patients. The data can also be applied for the assessment of the influence of new therapeutic strategies on the rate of progression of renal failure in cystinotic patients.

Child, Preschool↗
PubMed1994

Characterization of the Han:SPRD rat model for hereditary polycystic kidney disease.

The Han:SPRD rat model for inherited polycystic kidney disease (PKD) was characterized (clinical parameters, morphology, immunohistochemistry and in situ hybridization). Homozygous animals died of uremia after three to four weeks with severe cystic transformation of virtually all nephrons and collecting ducts (serum urea: 616 +/- 195 mg/dl; kidney-to-body weight ratio: > 20%). In heterozygotes, slow progression of the disease led to death between the 12th and 21st month (median: 17 months; serum urea levels above 200 mg/dl). Kidney enlargement was moderate, and cysts were restricted to the cortex and outer medulla. Immunohistochemical markers showed that approximately 75% of the cysts were derived from the proximal tubule. Cystic transformation started in the proximal tubule with a sharp onset of basement membrane alteration and a loss of epithelial differentiation restricted to small focal areas. In these areas, alpha 1(IV) collagen and laminin B1 mRNA were enhanced as revealed by isotopic and non-isotopic in situ hybridization. Fibroblasts underlying the affected tubular portions were involved in matrix overexpression resulting in subepithelial accumulation of immunoreactive collagen IV and laminin. In later stages of cystic transformation distal nephron segments were affected as well. A reversal in epithelial polarity as judged from Na,K-ATPase-immunoreactivity was not observed. Renal immunoreactive renin-status was significantly decreased. Hematocrit was lowered in heterozygotes (40.4 +/- 5.8 vol% compared to 46.7 +/- 1.99 vol% in controls; P < 0.05) and total renal EPO mRNA was reduced to 36 +/- 14% of the mean value of control animals, whereas serum EPO levels were not significantly altered. We conclude that the Han:SPRD rat is a useful model for the study of human ADPKD since both diseases are similar in several aspects. The model is particularly suitable for the study of epithelial-mesenchymal interactions at the beginning of tubular cystic transformation.

Animals↗
PubMed1994

Progression of chronic renal failure in a rat strain with autosomal dominant polycystic kidney disease.

UNLABELLED: Recently, the existence of a rat strain exhibiting autosomal dominant polycystic kidney disease (PKD) resembling human PKD has been described. An exact description of the course of chronic renal failure in this strain, however, is still missing. Thus the aim of this study was to analyze the long-term course of renal failure in these rats. In addition, unilateral nephrectomy (UNX) was performed in order to evaluate the impact of UNX on the occurrence of uremia. Our data clearly revealed that 70-80% of all animals of this rat strain developed uremia within 21 months. Additionally, proteinuria and hypercholesterolemia occurred, while the blood pressure was fairly unaffected. Also a slight degree of anemia was noted. In this long-term study death was due to uremia. The median survival time was significantly shorter in UNX PKD (median 11.6 months) than in non-UNX PKD animals (17.0 months; log-rank test: p = 0.001). IN CONCLUSION: with respect to renal function this rat model resembles human PKD disease. Furthermore, we could demonstrate that UNX is suitable to accelerate the rate of progression of renal failure in this model.

Animals↗
PubMed1993

[Autoregulation of kidney circulation, glomerular filtration rate and plasma renin activity in spontaneously hypertensive rats and normotensive Wistar rats].

The autoregulation of renal blood flow (RBF), glomerular filtration rate (GFR) and the pressure dependent renin release into the circulation were studied in conscious chronically instrumented spontaneously hypertensive rats (SHR) and normotensive Wistar rats. Renal perfusion pressure was lowered by means of a suprarenal inflatable cuff on the abdominal aorta and was lowered in pressure steps of 10 mm Hg. Breakoff points for RBF- and GFR-autoregulation as well as the threshold for renin release were calculated using non-linear regression (breakpoint analysis). Wistar rats autoregulated RBF and GFR in a range between 110 and 90 mm Hg (breakoff points: RBF 88 +/- 2 mm Hg; GFR 92 +/- 3 mm Hg). Plasma-renin activity (PRA) showed a threshold of activation at 89 +/- 8 mm Hg. Breakoff points and threshold of renin release did not differ significantly from each other. SHR autoregulated RBF and GFR in a range between 160 and 100 mm Hg (breakoff points: RBF 104 +/- 6 mm Hg; GFR 99 +/- 4 mm Hg). The PRA increase had a threshold at 119 +/- 6 mm Hg. Breakoff points of RBF- and GFR-autoregulation did not differ significantly. In SHR the threshold of renin release was at a significantly higher pressure than the breakoff point of GFR-autoregulation. The comparison between Wistar rats and SHR revealed a significant shift of the RBF-autoregulation curve and the pressure-dependent renin release of SHR towards higher pressures (p < 0.05). The early increase of PRA in SHR suggests a role of the renin-angiotensin-system (RAS) in the autoregulation of GFR in SHR. Wistar rats seem to autoregulate GFR independently of the RAS. An activation of the sympathetic nervous system might take part in the rightward shift of the RBF- and GFR-autoregulation curve in SHR. The role of this altered autoregulatory pattern in the development of genetic hypertension remains to be investigated.

Animals↗
PubMed1993

Changing pattern of chronic renal failure and renal replacement therapy in children and adolescents: a 20-year single centre study.

We analysed the demographic data, clinical course and survival on different forms of renal replacement therapy (RRT) of 374 children and adolescents with chronic renal failure observed between 1969 and 1988 and compared the findings for the four subsequent 5-year periods. The proportion of children below 5 years of age rose from 21% to 47%. With time the incidence of glomerulonephritis increased and that of pyelonephritis decreased. As RRT became more common, more very young children and more adolescents were admitted to the study. In the last 5 years continuous ambulatory peritoneal dialysis (CAPD) and haemodialysis (HD) were performed to the same extent as the initial form of RRT. The time a subject had to wait for a first transplant decreased from 36 to 21 months. Between 1969 and 1988 overall survival on any form of RRT increased to 77% after 10 years of therapy. In the last observation period 2-year patient survival was 100% both on HD and CAPD. First cadaver graft survival after 4 years improved from 25% in 1969-1973 to 69% in 1984-1988.

Adolescent↗
PubMed1993

Chronic lead exposure in rats: effects on blood pressure.

The influence of Pb exposure on blood pressure was investigated in Wistar Kyoto, Sprague Dawley and stroke prone spontaneously hypertensive rats. In short-term experiments, a dose-dependent decrease of blood pressure was found with administration of Pb acetate in drinking fluid. This effect was more pronounced in young, male as compared to old, female animals. Pressor responses to noradrenaline and ANG II were decreased. In contrast, long-term Pb exposure of more than 1 year duration consistently caused hypertension. In SHR-sp a high proportion of animals died from cerebrovascular haemorrhage even before developing hypertension. Chronically Pb exposed hypertensive rats had increased plasma volume and total body sodium despite normal renal function. Plasma concentrations of catecholamines and PRA were normal. The results show a biphasic effect of Pb on blood pressure. An important role of renal sodium retention in chronic Pb-induced experimental hypertension is suggested.

Age Factors↗