Biomedical subjects

N Gretz

Publications and source records attributed to N Gretz.

At least 55 records · Page 3Linked to original sources

PubMed1997

Azotemia and extrarenal manifestations in old female Han:SPRD (cy/+) rats.

In humans suffering from polycystic kidney disease (PKD) a gender difference is seen with males exhibiting a faster rate of progression of chronic renal failure than females. The aim of this study was to examine renal function in female rats suffering from autosomal dominant PKD [Han:SPRD (cy/+)] and to look for the occurrence of extrarenal organ manifestations of PKD. In young (2 months) as well as in old female rats (21 months) relative kidney weight was greater in affected than unaffected animals. In contrast, only the old affected female rats developed azotemia (serum urea 95 +/- 124 mg/dl) and severe cystic kidney transformation. Furthermore, old affected female rats exhibited liver cysts (affected 42%; unaffected 3%) and pancreatic cysts (affected 69%; unaffected 15%). Liver cyst epithelia stained positive for cytokeratin 19, a marker for bile duct epithelia. By immunohistochemistry liver cysts exhibited a similar extracellular matrix composition as observed in renal cysts of the same animals (staining positive for laminin, fibronectin and heparan sulfate proteoglycan, but not collagen I). This study proves PKD in the Han:SPRD (cy/+) rat model to be a truly multiorgan disease with a close resemblance of the human disease.

Age Factors↗

PubMed1997

Molecular genetic identification of families with juvenile nephronophthisis type 1: rate of progression to renal failure. APN Study Group. Arbeitsgemeinschaft für Pädiatrische Nephrologie.

Familial juvenile nephronophthisis (NPH), an autosomal recessive cystic disease of the kidney, is the most common genetic cause of end-stage renal disease (ESRD) in the first two decades of life. A gene locus for nephronophthisis type 1 (NPH1) has been mapped by linkage analysis to chromosome 2q13. We performed a haplotype analysis in 16 NPH families with at least two affected patients with the typical history, clinical signs and histology of NPH using microsatellite markers of the NPH1 genetic region. By demonstration of a recombinant event marker D2S1893 was identified as a novel centromeric flanking marker to the NPH1 critical genetic region. Absence of linkage to the NPH1 locus in six NPH families confirmed the existence of at least one additional gene locus for NPH. Linkage to the NPH1 locus was demonstrated in 10 families. In 8 of these families a homozygous deletion was identified. These data permit for the first time the study of the development of renal failure in a subset of NPH1 families, which is most likely homogeneous with regard to the responsible gene locus. We present a statistical description of serial serum creatinine measurements in NPH1. Analysis of renal death revealed a median of 13.1 years. Age-dependent quartiles were generated for serum creatinine. In summary, the new marker provides a diagnostic tool to aid in the diagnosis of NPH, while the progression charts offer a standard for an assessment of the rate of progression to ESRD for patients with NPH1 to be used in future therapeutic trials and for a prediction of the individual course of the disease.

DNA, Satellite↗

PubMed1997

Renal osmotic stress-induced cotransporter: expression in the newborn, adult and post-ischemic rat kidney.

The renal osmotic stress-induced cotransporter (ROSIT), a new putative member of a family of organic solute transporters, is highly expressed in the kidney. Our in situ hybridization data now reveal that large amounts of ROSIT mRNA can be found in the S3 segment of the proximal tubule. In the developing kidney, ROSIT mRNA is expressed after the S-shaped body stage. Because the S3 segment is the major site of damage in the post-ischemic kidney, we evaluated alterations in ROSIT mRNA expression after ischemic acute tubular necrosis. Renal osmotic stress-induced cotransporter mRNA levels were already decreased eight hours post-ischemia. At seven days post-ischemia, ROSIT mRNA reappeared in a mosaic pattern in the regenerating S3 segment, being fully expressed three weeks after the insult except for focal areas. The exact localization of this putative osmolyte transporter in the kidney, together with that of other known osmolyte transporter will contribute to a better understanding of the mechanism of medullary osmolyte accumulation and its vectorial transport.

Age Factors↗

PubMed1997

Location of the first genetic locus, PKDr1, controlling autosomal dominant polycystic kidney disease in Han:SPRD cy/+ rat.

The Han:SPRD cy/+ strain develops a form of slowly progressive disease that appears similar in many respects to that seen in the autosomal dominant polycystic kidney disease (ADPKD) in humans. We have performed a total genome scan in an experimental backcross population derived from affected Han:SPRD cy/+ rat (PKD) and non-affected Wistar Ottawa Karlsburg rat (WOK) using 117 microsatellite markers. The genetic dissection of PKD allowed us to map on rat chromosome 5, a quantitative trait locus (QTL) controlling PKD, kidney mass and plasma urea concentration. The homology region is likely to reside on human chromosome 8. The gene responsible for PKD in Han:SPRD cy/+ rat is neither PKD1, localised on human chromosome 16, nor PKD2, localised on human chromosome 4. Therefore, we propose that this new locus be denoted PKDr1. The detection of the PKDr1 locus and associated QTL should accelerate research into the genetic causes of ADPKD.

Animals↗

PubMed1997

Differentiation and cell polarity during renal cyst formation in the Han:SPRD (cy/+) rat, a model for ADPKD.

Despite the recent positional cloning of genes responsible for autosomal dominant polycystic kidney disease (ADPKD), the exact pathogenetic mechanisms underlying this disorder are still unclear. To learn more about cyst formation, we investigated cell differentiation and cell polarity in the Han:SPRD (cy/+) rat between 21 days and 60 wk of age. At early stages of cyst development, alkaline phosphatase, aquaporin-1, NaSi-1 cotransporter, and Na(+)-K(+)-adenosinetriphosphatase (Na(+)-K(+)-ATPase) were expressed normally. Clusterin mRNA was only sparsely expressed at the onset of cystic degeneration and increased thereafter, being highest in noncystic nephron segments. In cyst wall cells, clusterin on the one hand and alkaline phosphatase, aquaporin-1, NaSi-1-cotransporter, and Na(+)-K(+)-ATPase on the other were expressed in a mutually exclusive fashion. No change in cell polarity could be observed at any stage. Our data therefore argue against a change in cell polarity and against an early arrest in normal tubular development during cyst formation in the Han:SPRD (cy/+) rat model of ADPKD but favor the hypothesis that tubular epithelia develop in an orderly fashion and degenerate thereafter.

Aging↗

PubMed1997

Influence of the renal endothelin system on the autoregulation of renal blood flow in spontaneously hypertensive rats.

The renal endothelin (ET) system has been claimed to play an important role in the regulation of renal blood flow (RBF) and sodium excretion in primary hypertension. The aim of the present study was to investigate the contribution of the endogenous ET system in the autoregulation of total RBF, cortical blood flow (CBF), pressure-dependent plasma renin activity (PRA) and pressure natriuresis in spontaneously hypertensive rats (SHR) by means of the combined (A/B) ET-receptor antagonist, bosentan. In anesthetized rats, RBF was measured by transit-time flow probes and CBF by laser flow probes. During the experiments, the rats received an intrarenal infusion of either bosentan (1 mg/kg/h) or vehicle. Renal perfusion pressure (RPP) was lowered in pressure steps of 5 mm Hg with a servo-controlled electropneumatic device via an inflatable suprarenal cuff. Bosentan had no effect on resting RPP, CBF, PRA and renal sodium excretion, whereas RBF was lowered by 30% (p < 0.05). Furthermore after bosentan the rats revealed a complete loss of RBF autoregulation. In contrast no changes in autoregulation of CBF, pressure-dependent PRA and pressure natriuresis were observed. Our findings demonstrate a significant impairment in total RBF autoregulatory ability during renal ET-receptor blockade which is not confined to the cortical vessels. These data suggest that the renal ET system plays an important role in the dynamic regulation of renal blood flow in SHR.

Animals↗

PubMed1997

Organic anion secretion in polycystic kidney disease.

This study examined whether organic anion secretion contributes to fluid accumulation in cysts in polycystic kidney disease. Clearance and micropuncture studies were done on young (7 to 16 wk old), mostly male, heterozygous Han:SPRD cystic rats and healthy control littermate rats. Heterozygous Han:SPRD rats manifest a slowly progressive autosomal dominant polycystic kidney disease that closely resembles the human disorder. Left kidney GFR (polyfructosan clearance), in microl/min per 100 g body wt, averaged 331 +/- 36 (SD) in seven healthy rats and 278 +/- 75 in seven cystic rats. The maximal rate of p-aminohippurate (PAH) secretion, in micromol/min per 100 g body wt, averaged 0.94 +/- 0.24 in healthy rats and 0.83 +/- 0.11 in cystic rats. In these young rats, there were no significant differences in GFR or the maximal rate of PAH secretion despite the presence of cystic disease. Using fluorescence microscopy, it was found that 27 of 29 proximal cysts secreted sulfonefluorescein, an organic anion transported by the PAH system. Transmission electron micrographs of superficial cysts that had secreted sulfonefluorescein demonstrated the presence of both normal-appearing and poorly differentiated proximal tubule cells. Segments of superficial proximal convoluted tubules or cysts, isolated by upstream and downstream wax blocks, failed to accumulate fluid when PAH was infused intravenously. With the stationary microperfusion technique, PAH secretion by both normal and cystic nephrons was demonstrated. It is concluded that most proximal cystic epithelia retain the ability to secrete organic anions. Secretion of organic anions, however, does not appear to contribute in any substantial way to fluid accumulation in cysts in the rat kidney.

Animals↗

PubMed1996

[Chronic recurrent subileus due to Strongyloides stercoralis infection under immunosuppressive therapy].

HISTORY AND CLINICAL FINDINGS: A 33-year-old woman from Laos was admitted due to recurrent vomiting and weight loss. Since one year, she was receiving immunosuppressive therapy (azathioprine 50 mg/d and methylprednisolone 18 mg/d) for a mixed connective tissue disease. Because of a drug induced Stevens-Johnson-Syndrome one month earlier high doses of methylprednisolone (100 mg/d intravenously) had been administered. The patient's general condition was reduced. Examination elicited a mild pain in the middle abdomen on palpation but no resistance or tumour. The differential diagnosis included obstructive and (or) inflammatory disease of the gastrointestinal tract. INVESTIGATIONS: Elevated IgE-levels (1111 IU/ml; normal up to 100 IU/ml) and eosinophilia (8%) lead to the suspicion of a helminthiasis. Oesophagogastroduodenoscopy showed a significant duodenal stenosis. Duodenal biopsy revealed a severe infestation with Strongyloides stercoralis. Stool examinations were negative though. TREATMENT AND COURSE: With administration of thiabendazole (2 g/d) a rapid recovery was noted. A second oesophagogastroduodenoscopy one week after the onset of therapy revealed no further stenosis. Since there was no activity of the mixed connective tissue disease the methylprednisolone dosage was reduced and the administration of azathioprine was ceased. 3 weeks after beginning of treatment the patient was discharged in improved condition. CONCLUSION: In immunocompromised patients suffering from gastrointestinal complaints who have been in endemic areas an infection with Strongyloides stercoralis should be excluded. Without treatment, this helminthiasis may be fatal.

Adult↗

PubMed1996

Tubular gelatinase A (MMP-2) and its tissue inhibitors in polycystic kidney disease in the Han:SPRD rat.

Thickening of the tubular basement membrane is one of the hallmarks of the polycystic kidney disease (PKD). The present study was conducted to investigate the potential role of the matrix metalloproteinase-2 (MMP-2) and its specific tissue inhibitors (TIMP-1 and TIMP-2) in the accumulation of matrix components in PKD. As a model of PKD, two-month-old heterozygous Han:SPRD rats, which are at an early stage of cystogenesis, were used. MMP-2, but not MMP-9 (gelatinase B) nor MMP-3 (stromelysin) could be detected in proximal tubules of the normal rat kidney. The presence of the inhibitors TIMP-1 and TIMP-2 was confirmed on the mRNA level. In tubules from PKD rats MMP-2 activity was lower (31 +/- 8 vs. 58 +/- 7 U/prep., N = 9, P < 0.05), mRNA of MMP-2 was reduced 4.2 +/- 0.6-fold (N = 4, P < 0.05) and enzyme protein was depressed 3.8 +/- 0.8-fold (N = 4, P < 0.05). By contrast, TIMP-1 mRNA was 9.0 +/- 1.1-fold and TIMP-2 mRNA 3.8 +/- 0.7-fold (N = 4, P < 0.05) elevated over controls. Cyst fluid from homozygous rats contained MMP-2 protein and activity. These findings indicate that tubular MMP-2 activity is reduced in PKD, due to down-regulation of MMP-2, up-regulation of TIMP-1 and TIMP-2, and luminal secretion of the enzyme. It is conceivable that these alterations relate to the enhanced matrix accumulation observed in the evolution of PKD.

Animals↗

PubMed1996

Alterations of cathepsins B, H and L in proximal tubules from polycystic kidneys of the Han:SPRD rat.

Abnormalities of tubular matrix metalloproteinases have been shown recently to occur early in the course of polycystic kidney disease (PKD). The present study was conducted to determine whether lysosomal cysteine proteinases were altered in proximal tubules from 2-month-old, heterozygous Han:SPRD rats. The activities of cathepsins B (-45%), H (-39%) and L (-37%) were significantly lower in proximal tubules from PKD rats as compared to healthy offspring. Enzyme proteins were also decreased (cath. B, 2.4 +/- 0.7-fold; cath. H, 1.9 +/- 0.6-fold; N = 4, P < 0.05), while mRNA levels for cathepsins B, H and L were not different. Tubular cystatin C, a major inhibitor of cathepsins, was normal with regard to protein and mRNA levels in PKD animals. The decrease in cathepsins in PKD was specific for tubules, as enzyme activities in glomeruli and liver tissue were unchanged and limited to the lysosomal compartment, since marker enzymes for cytoplasm, endoplasmatic reticulum and mitochondria were all normal. Intralysosomally, soluble enzymes like cathepsins and beta-NAG were decreased, while membrane-bound acid phosphatase was unchanged. The presence of cathepsins could be demonstrated in cyst fluid from homozygous PKD rats and urinary excretion of cathepsins was enhanced in heterozygous animals. Taken together, these findings indicate that the reduction in tubular cathepsins B, H and L was neither due to decreased gene expression nor to upregulation of specific inhibitors, but was likely due to enhanced apical secretion of these enzymes.

Animals↗

PubMed1996

Role of obstruction in autosomal dominant polycystic kidney disease in rats.

Kidney micropuncture and microdissection studies were carried out on heterozygous 2- to 4-month-old female and male Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD) and on normal controls, to determine whether cysts are obstructed. Pressures in proximal tubules and cysts were determined using a servo null device and were recorded before, during, and after intraluminal infusion of an isotonic equilibrium solution at 15 and 50 n1/min. Initial cyst pressures in nine cystic rats averaged 18.5 +/- 5.9 (SD) mm Hg, N = 49, significantly (P < 0.01) higher than in normal proximal tubules in four control rats, 14.3 +/- 1.6 mm Hg, N = 36. Pressures in non-cystic tubules in cystic rats, 16.8 +/- 4.4 mm Hg, N = 25, were not significantly different from pressures in control kidneys or in cysts. When proximal tubules were microinfused at 15 nl/min in control rats, tubule pressure increased by 3.8 +/- 1.2 mm Hg, N = 24. In cysts, the response was highly variable. Twenty out of 33 microinfused cysts (61%) showed responses similar to normal tubules and were considered to be nonobstructed; 13 (39%) showed large pressure increases upon microinfusion, sometimes to values over 100 mm Hg (obstructed cysts). Left kidney inulin clearance (in microliter/min. 100 g body wt) averaged 335 +/- 65 (N = 4) in control rats and 344 +/- 144 (N = 9) in cystic rats; at this early stage of the disease no decline in GFR was seen. Weights of cystic kidneys were twice those of normal animals. Microdissection and scanning electron microscopy revealed the presence of intraluminal casts and debris and constrictions between cysts that would impede fluid flow. We conclude that obstruction is a frequent, early event in PKD and, when present, promotes cyst enlargement. Since many cysts are not obstructed, we suggest that factors other than fixed obstruction initiate cyst formation.

Anesthesia↗

PubMed1996

Murine models of polycystic kidney disease.

The current knowledge of human polycystic kidney disease (PKD)--its morphology as well as the current biochemical and molecular understanding of the disease- has been enormously aided by the existence of a variety of animal models. In mice, several spontaneous mutations have been identified that give rise to PKD. Furthermore, it has been possible to create experimental models of renal cystic disease by genetic manipulation. All these different models have been very informative in studying the role of growth hormones, cell differentiation and hyperplasia, ionic transport, oncogene expression and changes in extracellular matrix (ECM) composition during the development of PKD. Furthermore, they have allowed investigators to test different therapeutic approaches in vivo. This article will review the characteristics of the most common murine models of PKD, some of their current uses and the future role of these animal models in the understanding of human renal cystic disease.

Animals↗

PubMed1996

Rat models of autosomal dominant polycystic kidney disease.

Several rat models of polycystic kidney disease (PKD) have been published. The only rat model of autosomal dominant polycystic kidney disease currently used is the so-called Hannover rat (Han:SPRD cy/+). This model is characterized by a slow progression of uraemia, proteinuria and hyperlipidaemia. Histological changes clearly resemble those seen is human PKD. The localization of Na+/K(+)-ATPase correlating with the phenotype of the cysts--basal in moderately expanded and apical in highly expanded cysts--suggests that the mislocation of the Na+/K(+)-ATPase is involved in the mechanism of cyst expansion rather than formation, and a consequence of cell dedifferentiation rather than an initial event. Of note is a considerable gender difference in disease severity. Disease anticipation or genetic imprinting does not occur. In addition to gender, a number of interventions influence the progression rate: acceleration is noted after unilateral nephrectomy, the induction of acidosis, chloride feeding or an increased protein intake; slowing down of the course occurs after the induction of alkalosis and castration, and after treatment with lovastatin and methylprednisolone. Thus the Han:SPRD cy/+ rat represents the only well-documented rat model of autosomal dominant PKD resembling a number of features of the human disease.

Animals↗

PubMed1996

In vitro formation of cysts derived from a rat model of autosomal dominant polycystic kidney disease.

In this study, we report a model of spontaneous cyst formation in vitro and a procedure to obtain large quantities of cysts from polycystic rat kidney cells. Furthermore, we assess the effects of epidermal growth factor, a modulator of morphogenesis, and of taxol, a stabilizer of microtubules, which has recently been proposed as a useful treatment of human polycystic kidney disease (PKD). It is anticipated that data generated from in vitro studies using cysts from PKD-affected rat kidneys may yield further insights to the pathophysiological and cellular basis of fatal renal cyst formation processes, and may lead to specific therapeutic strategies directed at controlling the growth of cysts, thereby reducing the number of animal tests.

Animals↗

PubMed1996

Dialysis in rats with acute renal failure: evaluation of three different dialyzer membranes.

Exposure to complement-activating cellulosic dialysis membranes has been claimed to adversely affect the course of acute renal failure (ARF). To test this hypothesis, male Sprague-Dawley rats were allocated to 2 groups: in Group 1, ARF was induced by bilateral renal artery clamping whereas in Group 2, animals underwent a sham procedure. In each group, rats were further allocated to undergo hemodialysis with either a Cuprophan, a Hemophan, or a polyacrylonitrile minidialyzer on Days 4 and 8 after surgery, or no dialysis. Renal function was measured by inulin clearance on the days after dialysis. Additionally, total complement activity (CH50) was estimated on Days 1, 2, 4, and 8, and complement factor C3 was detected immunohistochemically. The degree of renal failure and the rate of recovery of renal function were similar in all the ARF groups irrespective of whether they had undergone dialysis or not, or of the type of the dialysis membrane. Furthermore, there were no significant differences in the course of CH50 or in the amount and distribution of complement factor C3 in the kidney tissue between the rats of Groups 1 and 2. Our findings refute the hypothesis that in ischemic ARF exposure to complement-activating cellulosic dialysis membranes impairs the recovery of renal function in rats.

Acrylic Resins↗

PubMed1996

Outcome of idiopathic membranoproliferative glomerulonephritis in children. Arbeitsgemeinschaft Pädiatrische Nephrologie.

The aim of this multicentre study was to analyse the long-term outcome of idiopathic membranoproliferative glomerulonephritis (MPGN) according to histological type and to the presence of C3 nephritic factor. Fifty patients aged 2-14 years at the onset of the study were followed over 2-20 years; 26 patients had MPGN type I, 17 had type II and 7 had type III. Treatment was variable. At the last observation, 30 patients had reached terminal and four pre-terminal renal failure. The median survival probability until renal death was 15.3, 8.7 and 15.9 years for disease types I, II and III respectively (difference between MPGN types I + III versus type II: p = 0.013). The presence of an initial nephrotic syndrome was associated with a more rapid progression (p = 0.018). C3 nephritic factor was of no prognostic value. We conclude that the outcome of MPGN mainly depends on the histological type observed.

Adolescent↗

PubMed1996

Presence of renin within intramitochondrial dense bodies of the rat adrenal cortex.

It has been suggested that tissue-specific expression of the genes of the renin-angiotensin system (RAS) leads to local generation of angiotensin (ANG) II with specific physiological implications. We demonstrate here that an intracellular RAS exists in adrenal glomerulosa cells; 60 h after bilateral nephrectomy and hemodialysis, renin and prorenin were eliminated from the circulation, whereas intra-adrenal renin content increased (control rats: 2 +/- 0.5 ng ANG I.mg-1.h-1; anephric rats: 25 +/- 2). Thus renin is produced locally within adrenal cells. We obtained immunocytochemical and biochemical evidence for the presence of renin within intramitochondrial dense bodies of the zona glomerulosa. After nephrectomy, dense bodies increased in number, size, and renin content (control rats: 2.5 +/- 0.7 ngANGI.mg-1.h-1; anephric rats: 43 +/- 7). Angiotensin-converting enzyme (ACE) was also present within mitochondria and their dense bodies. In addition, in adrenal cortex of anephric rats, giant dense bodies were observed, which contain renin and strongly react with an anti-angiotensinogen antibody. The localization of renin, ACE, and angiotensinogen at these sites provides new evidence for the existence of an intracellular adrenal RAS.

Adrenal Cortex↗

PubMed1996

Recovery from ischemic acute renal failure: independence from dialysis membrane type.

Exposure to complement-activating cellulosic dialysis membranes has been claimed to adversely affect the course of acute renal failure. To test this hypothesis, male Sprague-Dawley rats were allocated to two groups: in group I, acute renal failure was induced by bilateral renal artery clamping, while group II animals underwent a sham procedure. In each group, the rats were further allocated to undergo hemodialysis with either a Cuprophan, a Hemophan, or a PAN miniDialyzer membrane 3 and 7 days after surgery or no dialysis. The renal function was measured by inulin clearance on the days following dialysis. Temporary occlusion of the renal arteries led to a rapid increase in serum urea and creatinine levels that peaked between 24 and 48 h after surgery and declined slowly thereafter. Peak urea values were similar in the acute renal failure groups. The hemodialysis sessions were well tolerated. Degree and rate of recovery were similar in all acute renal failure groups irrespective of whether they underwent dialysis or not or the type of the dialysis membrane. Complete recovery was observed in all the acute renal failure groups by the end of the observation period. Our findings refute the hypothesis that in ischemic acute renal failure exposure to complement-activating cellulosic dialysis membranes impairs the recovery of renal function.

Acute Kidney Injury↗