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Biomedical subjects

S Nielsen

Publications and source records attributed to S Nielsen.

At least 145 records · Page 8Linked to original sources
PubMed1999

Relationship between urinary albumin excretion, body composition, and hyperinsulinemia in normotensive glucose-tolerant adults.

OBJECTIVE: Elevated urinary albumin excretion (UAE) has been associated with insulin resistance and is suggested to be elevated in prediabetic individuals. Upper body obesity, especially visceral obesity, predicts insulin resistance and development of type 2 diabetes. We examined whether UAE clusters with obesity-associated insulin resistance traits in healthy glucose-tolerant normotensive subjects. RESEARCH DESIGN AND METHODS: There were 49 volunteers with a wide range of body fat and body fat distribution studied. All had normal blood pressure and glucose tolerance and were maintained on a controlled diet for 2 weeks. UAE was assessed from three overnight urine collections, and body composition was assessed by whole-body dual-energy X-ray absorptiometry scanning and abdominal computed tomography scanning. RESULTS: Fasting insulin and insulin responses to oral glucose were significantly increased in obese subjects, who also tended to have more dyslipidemia, greater blood pressure, and more visceral fat than lean subjects. These differences were more apparent in upper body obese subjects. UAE was normal in obese and upper body obese subjects and not different from that of lean subjects. UAE ranged from 0.3 to 8.3 micrograms/min in lean subjects and from 0.2 to 7.2 micrograms/min in obese subjects. UAE was not significantly correlated with body composition, plasma insulin, glucose, or lipids. CONCLUSIONS: Obese subjects (even upper body obese subjects) with increased visceral and total body fat, high plasma insulin and triglycerides, and low HDL cholesterol concentrations do not have elevated UAE. This suggests that UAE is not closely associated with these characteristics and implies a later onset of abnormal albuminuria in the course of the insulin resistance syndrome.

Adipose Tissue↗
PubMed1999

Molecular identification and immunolocalization of the water channel protein aquaporin 1 in CBCECs.

PURPOSE: Water channel proteins are important pathways for water movements across cell membranes, including those in the corneal endothelium that contribute to the fluid transport mechanism essential in maintaining corneal transparency. This study was conducted to identify and locate the water channel protein(s) in cultured bovine corneal endothelial cells (CBCECs). METHODS: Poly(A)+ RNA was isolated from CBCECs, and MMLV reverse transcriptase and random hexamer primers were used to generate a cDNA pool by reverse transcription-polymerase chain reaction (RT-PCR). Two specific degenerate primers were synthesized based on consensus sequences from the major intrinsic lens protein superfamily; a "touchdown" PCR protocol accommodated the degeneracy. Immunolocalization was performed by incubating sections of CBCECs with an antibody against human aquaporin 1 (AQP1). Cryosections (0.85 microm) of CBCECs were used for light microscopy, and 800-A ultrathin cryosections were used for electron microscopy (EM). RESULTS: A 372-bp fragment was isolated. Its encoded amino acid sequence was 100% identical with that of bovine AQP1 (AQP2_bovin). CBCECs reacted strongly with the anti-AQP1 antibody, and the labeling was selectively localized to the plasma membrane by light microscopy. Subcellular localization by EM revealed immunoreactivity with the inner leaflets of the plasma membrane. CONCLUSIONS: The identity of the aquaporin, its abundance, and its membrane location suggest that it is a major pathway for fluid flow across endothelial cell membranes. This is consistent with transcellular endothelial fluid transport.

Amino Acid Sequence↗
PubMed1999

Epidemiology of juvenile chronic arthritis: risk dependent on sibship, parental income, and housing.

OBJECTIVE: We studied the socioeconomic background of children with juvenile chronic arthritis (JCA) diagnosed during the years 1988-91 in Denmark. The working hypothesis is that JCA may be triggered by one or several different infectious agents and that the amount of exposure to infectious agents in infancy and childhood affects the risk of JCA. METHODS: In this case-control study, we investigated socioeconomic variables prior to disease onset from national registers, primarily the Fertility Database of Statistics Denmark, in a national cohort of all 220 known cases of JCA fulfilling the EULAR criteria incident during the years 1988-91, identified from national and local diagnosis registers. There were 4 controls per case, matched for sex, age, and county of residence. Socioeconomic variables as risk factors were quantified by odds ratios, which are equivalent to relative risks of contracting JCA if exposed to a risk factor. RESULTS: Three socioeconomic variables were significantly and mutually independently associated with the risk of developing JCA during the following year. An only child had a risk of JCA 1.6 times that of a child with siblings. Children whose parents had a high income had a relative risk of 1.9. Children living in an urban flat had a risk 2.7 times that of children living on a farm. We found no space-time clustering of cases and no cyclical variations of incidence rates. CONCLUSION: The absence of clustering and of seasonal variation does not support a theory of triggering by infection. The hitherto unreported effects of the socioeconomic variables on the risk of JCA are of the same order of magnitude as reported for certain HLA alleles. Our findings do not lend full support to either of the 2 mechanisms, that growing up under either hygienic or unhygienic conditions increases the risk of JCA, and lack an obvious biological explanation.

Adolescent↗
PubMed1999

Expression of aquaporin 1 (AQP1) water channels in human labial salivary glands.

Aquaporin (AQP) water channels are widely expressed in the membranes of fluid-transporting epithelia. Despite the fact that salivary glands are the site of considerable water movement, relatively little is known about the role of aquaporins in human salivary glands. We have examined the expression of AQP1 in human parotid, sublingual and labial salivary glands. Total RNA was extracted from glandular tissue obtained from surgery or biopsy. The presence of AQP1 mRNA was demonstrated in each of the three glands by RT-PCR using primers specifically designed for human AQP1. The PCR product from the labial gland RNA was further amplified with nested primers and the sequence confirmed by automated fluorescent DNA sequencing. The cleaned first PCR product from these glands was then used as a 32P-labelled hybridization probe in a Northern analysis which confirmed the presence of significant amounts of AQP1 transcript in all three glands. AQP1 expression was also demonstrated in cryosections of human labial glands by immunohistochemistry using peroxidase-linked antibodies. Antibody labelling was most prominent in the capillaries but was also evident in the basal regions of the labial gland acini, and may therefore be associated with the serous demilunes which are believed to be a significant site of fluid movement.

Adult↗
PubMed1999

The role of nitric oxide in L-arginine-stimulated growth hormone release.

Nitric oxide (NO) exerts widespread and fundamental physiological effects. It is identical to the so-called endothelium-derived relaxing factor which regulates vascular tone. It has also been demonstrated to act as a neurotransmitter in both the peripheral and central nervous systems. NO is generated from L-arginine catalyzed by the NO synthases (NOS), of which two constitutive and one inducible form exist. NO stimulates the soluble guanylate cyclase which generates cyclic guanosine monophosphate (cGMP), that is believed to mediate the effects of NO. Recently, however, it has also been shown that NO is generated non-enzymatically from both L- and D-arginine by reaction with peroxide. The role of this pathway in the neuroregulation of growth hormone (GH) secretion has not yet been investigated. In rats, NO stimulates secretion of GH-releasing hormone (GHRH) and thus increases secretion of GH. However, it has also been observed that GHRH, in turn, increases production of NO in somatotroph cells, which subsequently blunts GH secretion. In humans, L-arginine stimulates pituitary GH release, but the mechanism is not fully clarified. Most studies suggest that an inhibition of somatostatin secretion is responsible for the effect. Infusion of low doses of the NOS inhibitor N(G)-nitro-L-arginine methyl ester have been shown not to change L-arginine-stimulated GH secretion. The effect of the NO donor molsidomine has also been found to have no influence on GH secretion. We investigated whether intravenous infusion of the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA) influenced L-arginine-stimulated GH secretion in healthy young men. All subjects were examined twice in random order. On both occasions L-arginine was infused intravenously. This treatment was accompanied by either: L-NMMA co-infused or a saline infusion. Plasma cGMP was unchanged and identical in the two treatment groups, and the urine cGMP/creatinine ratio increased identically during both examinations. GH secretion increased significantly during L-arginine infusion and was not influenced by co-infusion of L-NMMA. There is so far no evidence that L-arginine stimulates GH release via NO production. However, it remains to be elucidated whether the doses of different L-arginine inhibitors/NO donors used in the previous studies were insufficient.

Animals↗
PubMed1998

Direct immunogold labeling of aquaporin-4 in square arrays of astrocyte and ependymocyte plasma membranes in rat brain and spinal cord.

Aquaporin (AQP) water channels are abundant in the brain and spinal cord, where AQP1 and AQP4 are believed to play major roles in water metabolism and osmoregulation. Immunocytochemical analysis of the brain recently revealed that AQP4 has a highly polarized distribution, with marked expression in astrocyte end-feet that surround capillaries and form the glia limitans; however, the structural organization of AQP4 has remained unknown. In freeze-fracture replicas, astrocyte end-feet contain abundant square arrays of intramembrane particles that parallel the distribution of AQP4. To determine whether astrocyte and ependymocyte square arrays contain AQP4, we employed immunogold labeling of SDS-washed freeze-fracture replicas and stereoscopic confirmation of tissue binding. Antibodies to AQP4 directly labeled approximately 33% of square arrays in astrocyte and ependymocyte plasma membranes in rat brain and spinal cord. Overall, 84% of labels were present beneath square arrays; 11% were beneath particle clusters that resembled square arrays that had been altered during fixation or cleaving; and 5% were beneath the much larger areas of glial plasma membrane that were devoid of square arrays. Based on this evidence that AQP4 is concentrated in glial square arrays, freeze-fracture methods may now provide biophysical insights regarding neuropathological states in which abnormal fluid shifts are accompanied by alterations in the aggregation state or the molecular architecture of square arrays.

Animals↗
PubMed1998

[Mortality of anorexia nervosa in Denmark 1970-1987].

Eight hundred and fifty-three patients were admitted to psychiatric institutions in Denmark with anorexia nervosa between 1970 and 1986. Based on register information, 50 deaths were recorded during a mean follow-up period of 7.8 years. Amongst these, five were males and 45 females. The standardized mortality ratio (SMR) was 9.1 in both sexes. The SMR was maximal during the first year after index admission. Suicide was the dominant cause of death amongst subjects who died from unnatural causes (18 of 22 cases). Among those who died from natural causes (24 subjects), 13 individuals died from anorexia nervosa, and 11 individuals died from other illnesses.

Adolescent↗
PubMed1998

Aquaporin-4 water channel protein in the rat retina and optic nerve: polarized expression in Müller cells and fibrous astrocytes.

The water permeability of cell membranes differs by orders of magnitude, and most of this variability reflects the differential expression of aquaporin water channels. We have recently found that the CNS contains a member of the aquaporin family, aquaporin-4 (AQP4). As a prerequisite for understanding the cellular handling of water during neuronal activity, we have investigated the cellular and subcellular expression of AQP4 in the retina and optic nerve where activity-dependent ion fluxes have been studied in detail. In situ hybridization with digoxigenin-labeled riboprobes and immunogold labeling by a sensitive postembedding procedure demonstrated that AQP4 and AQP4 mRNA were restricted to glial cells, including MHller cells in the retina and fibrous astrocytes in the optic nerve. A quantitative immunogold analysis of the MHller cells showed that these cells exhibited three distinct membrane compartments with regard to AQP4 expression. End feet membranes (facing the vitreous body or blood vessels) were 10-15 times more intensely labeled than non-end feet membranes, whereas microvilli were devoid of AQP4. These data suggest that MHller cells play a prominent role in the water handling in the retina and that they direct osmotically driven water flux to the vitreous body and vessels rather than to the subretinal space. Fibrous astrocytes in the optic nerve similarly displayed a differential compartmentation of AQP4. The highest expression of AQP4 occurred in end feet membranes, whereas the membrane domain facing the nodal axolemma was associated with a lower level of immunoreactivity than the rest of the membrane. This arrangement may allow transcellular water redistribution to occur without inducing inappropriate volume changes in the perinodal extracellular space.

Animals↗
PubMed1998

Immunocytochemical localization of aquaporin 1 in the rat retina.

Aquaporins transport water through membranes of various tissues, thereby playing crucial roles in a number of physiological processes. Aquaporin 1 (AQP1, also known as CHIP, channel forming integral membrane protein of 28 kDa) is the first identified protein to function as a water channel and has been recently shown to be present in the rat retina. This study was conducted to examine the cellular localization of AQP1 in the rat retina by immunocytochemistry using antisera against AQP1. The AQP1-like immunoreactivity was present in a certain population of amacrine cells and in the proximal processes of Müller cells. Thus, AQP1 appears to be important in the retinal homeostasis.

Animals↗
PubMed1998

[Substrate metabolism in untreated and treated thyrotoxicosis].

Accelerated metabolism is a hallmark of thyrotoxicosis, but the underlying biochemical mechanisms are incompletely understood. In order to elucidate these metabolic events further, we studied 12 patients with newly diagnosed diffuse (10 patients) or nodular (two patients) toxic goitre (ten women, two men; age 42.8 +/- 3.2 yr; BMI: 21.6 +/- 0.7 kg/m2) before ("TOX") and after ("TRE") 11.2 +/- 1.0 weeks treatment with methimazole and compared these patients to a control group ("CTR") of 11 subjects (nine women, two men; age 40.5 +/- 3.9 yr; BMI 22.5 +/- 1.0 kg/m2). All were studied for three hours in the basal state, using indirect calorimetry, isotope dilution for measurement of glucose turnover and the forearm technique for assessment of muscle metabolism. Prior to treatment patients with thyrotoxicosis were characterized by: Increased (p < 0.05) levels of T3 (3.75 +/- 0.23 [TOX], 1.89 +/- 0.08 [TRE] and 1.75 +/- 0.11 [CTR] nmol/l), resting energy expenditure (130.5 +/- 3.5 [TOX], 107.7 +/- 2.7 [TRE] and 106.3 +/- 3.1 [CTR] percent of predicted), protein oxidation (0.67 +/- 0.03 [TOX], 0.54 +/- 0.06 [TRE] and 0.46 +/- 0.05 [CTR] mg/kg/min), lipid oxidation (1.34 +/- 0.08 [TOX], 1.00 +/- 0.06 [TRE] and 1.02 +/- 0.04 [CTR] mg/kg/min), endogenous glucose production (2.51 +/- 0.13 [TOX], 1.86 +/- 0.12 [TRE] and 1.85 +/- 0.12 [CTR] mg/kg/min), non-oxidative glucose turnover (1.28 +/- 0.16 [TOX], 0.75 +/- 0.18 [TRE] and 0.71 +/- 0.11 [CTR] mg/kg/min) and a 50% increase in total forearm blood flow. Glucose oxidation (1.23 +/- 0.09 [TOX], 1.13 +/- 0.10 [TRE] and 1.13 +/- 0.09 [CTR] mg/kg/min), exchange of substrates in the muscles of the forearm and circulating levels of insulin, C-peptide, growth hormone or glucagon were not influenced by hyperthyroidism. Propranolol (20 mg thrice daily) given to seven of the patients for two days did not affect circulating levels of thyroid hormones, energy expenditure or glucose turnover rates. These results suggest that all major fuel sources contribute to the hypermetabolism of thyrotoxicosis and that augmented non-oxidative glucose metabolism may further aggravate the condition. All abnormalities recede with medical treatment of the disease.

Adult↗
PubMed1998

[Insulin resistance among relatives of patients with NIDDM. Significance of physical fitness and muscle metabolism].

To explore the possible role of a reduced physical fitness for the diminished insulin sensitivity in first-degree relatives of NIDDM patients, 21 relatives and 22 matched control subjects were examined employing a hyperinsulinaemic (insulin infusion rate 0.6 mU/kg/min) euglycaemic clamp combined with the isotope dilution technique (3-3H-glucose), the forearm technique and indirect calorimetry. During hyperinsulinaemia glucose disposal (Rd) was significantly diminished in the relatives (p < 0.01). Maximal oxygen uptake (VO2 max) was 15% lower in the relatives than in the controls (p = 0.03). There was a highly significant correlation between Rd and VO2 max in both groups. In multiple linear regression analyses with Rd as the dependent variable VO2 max significantly determined the level of Rd (p < 0.01), whereas forearm blood flow and anthropometric data did not. We concluded that the insulin resistance in healthyfirst degree relatives of patients with NIDDM is associated with a diminished physical work capacity. Whether this finding is ascribable to environmental or genetic factors remains to be determined.

Adult↗
PubMed1998

Prevalence of eating disorders in Norwegian general hospitals 1990-1994: admissions per year and seasonality.

OBJECTIVE: To study the occurrence of eating disorders in patients admitted to somatic hospitals. METHOD: For all, approximately 3.3 million, admissions to Norwegian general hospitals in the period 1990-1994, admissions with the primary diagnoses for the eating disorders anorexia nervosa (AN) and bulimia nervosa (BN) were selected. Data on gender, age groups, emergency admission, different hospital types, length of stay, seasonal differences, and differences along the latitudes were related to the primary diagnosis. RESULTS: A small number of men with eating disorders were admitted; 9-17 times more women were admitted (140-183 female and 11-15 male admissions per year). The male/female ratio was on the mean 8% for the period. About two thirds to three fourths were emergency admissions. The mean length of stay was 12-19 days, and the median stay was 6-8 days. A significant (p = .03) season of admission was found. A significant number of admissions occurred in the beginning of March and a minimum in June. The best model was two harmonics without trend. DISCUSSION: There are few reports on eating disorders in somatic inpatients in the literature, but our results indicate that it is important to consider the general hospital in this connection. Bulimia nervosa was rather unusual in the present study, while anorexia nervosa was prevalent, specifically for women. Seasonality has rarely been reported in relation to hospitalization.

Adolescent↗
PubMed1998

Studies of renal aquaporin-2 expression during renal escape from vasopressin-induced antidiuresis.

In animal models of the syndrome of inappropriate antidiuresis (SIADH), sustained administration of vasopressin and water results in free-water retention and progressive hyponatremia for several days, which is then followed by escape from the vasopressin-induced antidiuresis. With the onset of vasopressin escape, water excretion increases despite sustained administration of vasopressin, allowing water balance to be re-established and the serum sodium to be stabilized at a steady, albeit decreased, level. Studies from our laboratories have investigated whether this escape phenomenon can be attributed to altered regulation of aquaporin water channels. After four-day pre-treatment with 1-deamino-[8-D-arginine]-vasopressin (dDAVP) by osmotic minipump, rats were divided into control (continued dDAVP) and water-loaded (continued dDAVP plus a daily oral water load) groups. A significant increase in urine volume in the water-loaded rats was observed by the second day of water loading, indicating escape from antidiuresis. The onset of escape coincided temporally with a marked decrease in renal aquaporin-2 protein (measured by semi-quantitative immunoblotting), which began at day 2 and fell to 17% of control levels by day 3. In contrast, there was no decrease in the renal expression of aquaporins 1, 3, or 4. The marked suppression of whole kidney aquaporin-2 protein was accompanied by a concomitant suppression of whole kidney aquaporin-2 mRNA levels. Immunocytochemical localization and differential centrifugation studies demonstrated that trafficking of aquaporin-2 to the plasma membrane remained intact during vasopressin escape. Additional studies have indicated that the observed down-regulation of aquaporin-2 expression also occurs in the renal cortex as well as the inner and outer medullas, and can be reversed simply by water restriction despite maintenance of hyponatremia. Our results therefore suggest that escape from vasopressin-induced antidiuresis is attributable, at least in part, to a vasopressin-independent and osmolality-independent decrease in aquaporin-2 water channel expression in the renal collecting duct. Similar mechanisms likely contribute to the phenomenon of escape from antidiuresis seen clinically in patients with SIADH as well.

Animals↗
PubMed1998

Mechanism of antidiuresis caused by bendroflumethiazide in conscious rats with diabetes insipidus.

1. The mechanism underlying the antidiuretic effect of thiazide diuretics in diabetes insipidus (DI) is unknown. This study addressed two specific questions: is the reduction in urine flow rate (V) related to a decrease in the delivery of fluid from the pars recta of the proximal tubules ('distal delivery'), and are there any changes in the expression and/or intracellular distribution of vasopressin stimulated water channels (AQP2) in the collecting ducts, during chronic thiazide-induced antidiuresis? 2. Nine Brattleboro rats with vasopressin-deficient DI were treated for 5 days with bendroflumethiazide (BFTZ), 9 mg kg(-1) day(-1) orally, and 9 Brattleboro rats were left untreated. BFTZ-treated DI rats showed a fall in V from approximately 200 to approximately 75 ml day(-1) and an increase in urine osmolality from approximately 130 to approximately 400 mosmol kg(-1). 3. BFTZ-induced antidiuresis was associated with a persistent loss of sodium, but not of potassium. After 5 days of treatment, clearance studies in conscious rats showed a tendency towards decreases in effective renal plasma flow (-7%), GFR (-12%) and lithium clearance (C(Li); used as marker for distal delivery) (-25%), compared with untreated controls, but none of these changes were statistically significant. There was no apparent relationship between C(Li) and V in BFTZ-treated or untreated DI rats. 4. BFTZ treatment did not change the expression of AQP2 in homogenates of cortex, outer or inner medulla from DI rats, or from normal Long Evans rats. Light and electron microscopic immunocytochemistry revealed no changes in intracellular distribution of AQP2 in principal cells from inner medullary collecting ducts of BFTZ-treated DI rats. 5. We concluded, (i) that although the antidiuretic effect of BFTZ in rats with DI is associated with a net loss of Na, the decrease in V shows no association with changes in distal delivery, as estimated by C(Li). (ii) Antidiuretic treatment with BFTZ does not alter the expression of subcellular distribution of AQP2 water channels in the collecting ducts. The mechanism underlying the chronic antidiuresis caused by thiazide diuretics in DI remains elusive.

Animals↗
PubMed1998

Select types of supporting cell in the inner ear express aquaporin-4 water channel protein.

Aquaporins (AQPs) confer a high water permeability on cell membranes and play important parts in secretory and absorptive epithelia in kidney and other organs. Here we investigate whether AQPs are expressed in the sensory epithelia of the inner ear, where a precise volume regulation is crucial. By use of specific antibodies it was found that the inner ear contains AQP1 and 4 while being devoid of detectable levels of AQP2, 3 or 5. Immunofluorescence and postembedding immunogold labelling revealed a strictly non-epithelial distribution of AQP1, confirming previous data. In contrast, AQP4 protein and mRNA (visualized by in situ hybridization) were concentrated in select types of supporting cell, including Hensen's cells and inner sulcus cells. Immunogold particles signalling AQP4 were confined to the basolateral plasma membrane of Hensen's cells and to the basal plasma membrane of Claudius cells and inner sulcus cells. AQP4 was also found in supporting cells of the vestibular end organs, but was absent from transitional epithelial cells and dark cells. Strong labelling for AQP4 and AQP4-mRNA was associated with the central part of the cochlear and vestibular nerves. Hair cells were consistently unlabelled. Our findings indicate that AQP4 may facilitate osmotically driven water fluxes in the sensory epithelia of the inner ear and thus contribute to the volume and ion homeostasis at these sites.

Animals↗
PubMed1998

Impaired aquaporin and urea transporter expression in rats with adriamycin-induced nephrotic syndrome.

Nephrotic syndrome is associated with abnormal regulation of renal water excretion. To investigate the role of collecting duct water channels and solute transporters in this process, we have carried out semiquantitative immunoblotting of kidney tissues from rats with adriamycin-induced nephrotic syndrome. These experiments demonstrated that adriamycin-induced nephrotic syndrome is associated with marked decreases in expression of aquaporin-2, aquaporin-3, aquaporin-4, and the vasopressin-regulated urea transporter in renal inner medulla, indicative of a suppression of the capacity for water and urea absorption by the inner medullary collecting duct. In contrast, expression of the alpha(1)-subunit of the Na,K-ATPase in the inner medulla was unaltered. Light and electron microscopy of perfusion-fixed kidneys demonstrated that the collecting ducts are morphologically normal and unobstructed. Inner medullary expression of the descending limb water channel, aquaporin-1, was not significantly altered, pointing to a selective effect on the collecting duct. Aquaporin-2 and aquaporin-3 expression was also markedly diminished in the renal cortex, indicating that the effect is not limited to the inner medullary collecting duct. Differential centrifugation studies and immunocytochemistry in inner medullary thin sections demonstrated increased targeting of aquaporin-2 to the plasma membrane, consistent with the expected short-term action of vasopressin on aquaporin-2 trafficking. The extensive down-regulation of aquaporin and urea transporter expression may represent an appropriate renal response to the extracellular volume expansion observed in nephrotic syndrome, but may occur at the expense of decreased urinary concentrating and diluting capacity.

Adenylyl Cyclases↗
PubMed1998

Concentrating defect in experimental nephrotic syndrone: altered expression of aquaporins and thick ascending limb Na+ transporters.

BACKGROUND: Several pathophysiological states associated with deranged water balance are associated with altered expression and/or intracellular distribution of aquaporin water channels. The possible role of dysregulation of thick ascending limb NaCl transporters, which are responsible for countercurrent multiplication in the kidney, has not been evaluated. METHODS: Semiquantitative immunoblotting and immunocytochemistry were carried out in the kidneys of rat with adriamycin-induced nephrotic syndrome and in vehicle-injected control rats. RESULTS: Preliminary studies confirmed the presence of a severe concentrating defect. Semiquantitative immunoblotting of outer medullary homogenates demonstrated a marked decrease in the abundance of three thick ascending limb Na+ transporters in nephrotic rats, namely the bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1), the type 3 Na/H exchanger (NHE-3), and the alpha 1-subunit of the Na-K-ATPase. These results are predictive of a decrease in the NaCl transport capacity of the medullary thick ascending limb and therefore a decrease in countercurrent multiplication. Immunocytochemistry of outer medullary thin sections demonstrated broad (but highly variable) suppression of BSC-1 expression in the outer medullas of adriamycin-nephrotic rats. There was also a large decrease in outer medullary expression of two collecting duct water channels (aquaporin-2 and -3) and the major water channel of the thin descending limb of Henle's loop (aquaporin-1). CONCLUSION: The concentrating defect in adriamycin-induced nephrotic syndrome in rats is a consequence of multiple defects in water and solute transporter expression, which would alter both the generation of medullary interstitial hypertonicity and osmotic equilibration in the collecting duct. Whether a similar widespread defect in transporter expression is present in idiopathic nephrotic syndrome is, at this point, untested.

Animals↗