Biomedical subjects

A C Eklöf

Publications and source records attributed to A C Eklöf.

At least 19 recordsLinked to original sources

PubMed2001

Increased blood pressure and loss of anp-induced natriuresis in mice lacking DARPP-32 gene.

Atrial natriuretic peptide (ANP) is an important regulator of sodium metabolism and indirectly of blood pressure. Evidence has accumulated that ANP regulates sodium metabolism through a cascade of steps involving an increase in the level of cGMP, activation of cGMP-dependent protein kinase (PKG), and inhibition of renal tubular Na+, K+-ATPase activity. One of the major substrates for PKG is DARPP-32. In the present study we observed that ANP does not induce natriuresis in mice that lack DARPP-32. In contrast, there was a 4-fold increase in urinary sodium excretion following ANP administration to wild type mice. ANP as well as Zaprinast, a selective inhibitor of cGMP phosophodiesterase, inhibited renal Na+, K+-ATPase activity in wild type mice but had no such effect in mice lacking DARPP-32. Mean arterial blood pressure, measured in conscious animals, was significantly increased in DARPP-32 deficient mice as compared to wild type mice. The results confirm that DARPP-32 acts as a third messenger in the ANP signaling pathway in renal tissue and suggest an important role of DARPP-32 in the maintenance of normal blood pressure.

Animals↗

PubMed2000

Combined antioxidant and COMT inhibitor treatment reverses renal abnormalities in diabetic rats.

The development and progression of diabetic nephropathy is dependent on glucose homeostasis and many other contributing factors. In the present study, we examined the effect of nitecapone, an inhibitor of the dopamine-metabolizing enzyme catechol-O-methyl transferase (COMT) and a potent antioxidant, on functional and cellular determinants of renal function in rats with streptozotocin-induced diabetes. Administration of nitecapone to diabetic rats normalized urinary sodium excretion in a manner consistent with the dopamine-dependent inhibition of proximal tubule Na,K-ATPase activity. Hyperfiltration, focal glomerulosclerosis, and albuminuria were also reversed by nitecapone, but in a manner that is more readily attributed to the antioxidant potential of the agent. A pattern of elevated oxidative stress, measured as CuZn superoxide dismutase gene expression and thiobarbituric acid-reactive substance content, was noted in diabetic rats, and both parameters were normalized by nitecapone treatment. In diabetic rats, activation of glomerular protein kinase C (PKC) was confirmed by isoform-specific translocation and Ser23 phosphorylation of the PKC substrate Na,K-ATPase. PKC-dependent changes in Na,K-ATPase phosphorylation were associated with decreased glomerular Na,K-ATPase activity. Nitecapone-treated diabetic rats were protected from these intracellular modifications. The combined results suggest that the COMT-inhibitory and antioxidant properties of nitecapone provide a protective therapy against the development of diabetic nephropathy.

Animals↗

PubMed1999

Mechanism of FK 506/520 action on rat renal proximal tubular Na+, K+-ATPase activity.

BACKGROUND: The neurotransmitter in renal sympathetic nerves, norepinephrine (NE), regulates the activity of proximal tubule (PT) Na+,K+-ATPase in a bidirectional manner via stimulation of alpha- and beta-adrenoceptors. The stimulatory alpha-adrenergic pathway is mediated by calcineurin, the target molecule for FK 506 and related compounds. We examined whether the FK 506 analogue FK 520, by interrupting the calcineurin-mediated alpha-adrenergic signaling pathway, enhance the inhibitory beta-adrenergic effect of NE on PT Na+,K+-ATPase activity. METHODS: The effects of three days of treatment with FK 520 were examined on rat renal PT Na+,K+-ATPase activity, measured as ouabain-sensitive ATP hydrolysis in single, microdissected PT segments. Renal function studies, including glomerular filtration rate (GFR) and urinary excretion of N-acetyl-3-D-glucoseaminidase (NAG), were examined using conventional clearance techniques after three days of treatment with FK 506. RESULTS: FK 520 treatment induced a pronounced and dose-dependent decrease in PT Na+,K+-ATPase activity. This effect was completely reversed by the competitive FK 520 antagonist, L 685 818, indicating that the effect was dependent on inhibition of calcineurin. To test whether the FK 520-induced decrease in Na+, K+-ATPase activity was mediated by enhanced beta-adrenoceptor signaling, the FK 520 effect was examined in rats pretreated with a beta-adrenoceptor antagonist (propranolol) or rats subjected to renal denervation. Both of these procedures prevented the FK 520-induced decrease in Na+,K+-ATPase activity. Thus, during FK 520 treatment, renal sympathetic nerves mediate an inhibitory effect on PT Na+,K+-ATPase activity via beta-adrenoceptors. Propranolol pretreatment also prevented FK 506-induced decreases in GFR and urinary excretion of NAG, an index of PT dysfunction. CONCLUSIONS: The results support the hypothesis that the net effect of the neurotransmitter NE on Na+,K+-ATPase activity is dependent on the balance between the alpha- and beta-adrenergic signaling pathways and suggest that agents that interfere with these pathways may, by altering the activity of tubular Na+,K+-ATPase, also alter the function of the renal tubular epithelial cell.

Animals↗

PubMed1998

The renal dopamine system.

Intrarenally formed dopamine induced natriuresis by inhibiting the activity of renal tubular Na/KATPase. This effect is mediated via a complex signal network, which includes inhibition of PP1 via the adenylyl cyclase-PKA-DARPP32 pathway and activation of PKC via the PLA2-arachidonic acid-20HETE pathway. The renal dopamine availability is a major determinant of the natriuretic effect of dopamine and is to a large extent modulated by the activity of COMT. The possibility that regulation of dopamine storage and release influences renal dopamine effects should be considered.

Adenylyl Cyclases↗

PubMed1998

Prenatal dexamethasone causes oligonephronia, sodium retention, and higher blood pressure in the offspring.

Recent reports have shown that low birth weight infants have a higher incidence of adult hypertension. These observations have stimulated a number of studies designed to evaluate the mechanisms of this phenomenon. In this study, fetal growth retardation was induced by treating pregnant rats with dexamethasone. After birth, pups whose mothers were treated with dexamethasone had a lower body and kidney weight and a lower number of glomeruli than control pups. Immunohistochemistry on treated kidneys demonstrated a marked reduction in the number of cells undergoing mitosis in the cortical nephrogenic zone. In the treated group, body and kidney weight normalized by 60 d of age, but blood pressure was significantly higher compared with controls (130+/-4 versus 107+/-1 mm Hg). In addition, GFR was significantly lower, albuminuria was higher, urinary sodium excretion rate and fractional sodium excretion were lower, and sodium tissue content was higher. In contrast, when pregnant rats were treated with a natural glucocorticoid (hydrocortisone) which is metabolized by the placenta, fetal development and adult blood pressure were normal. In conclusion, we found that high levels of maternal glucocorticoids impair renal development and lead to arterial hypertension in offspring. Even though renal mass eventually normalizes, glomerular damage as well as sodium retention occur and these factors may contribute to the development of hypertension.

Animals↗

PubMed1997

Rapid development of glomerulosclerosis in diabetic Dahl salt-sensitive rats.

Diabetic nephropathy tends to develop more readily in patients with a family history of hypertension and/or disturbances in sodium transport across the plasma membrane. This prompted us to study the renal effects of diabetes mellitus in a rat strain which is predisposed to develop salt-sensitive hypertension, the Dahl salt-sensitive rat. Diabetes is associated with several aberrations in the renal handling of sodium, such as elevation of tubular Na+, K+ATPase activity. This effect was more pronounced in Dahl salt-sensitive than in Dahl salt-resistant rats. Severe renal lesions, characteristic of the advanced phase of diabetic nephropathy are very rarely observed in rats with streptozotocin diabetes. However, 2 months after induction of diabetes, the Dahl salt-sensitive rats had morphological signs of advanced glomerular disease. The urinary albumin concentration was very high, but did not correlate with the blood pressure. Non-diabetic Dahl salt-sensitive rats as well as Dahl salt-resistant diabetic and non-diabetic rats had little or no signs of glomerular disease and consistently very low urinary albumin concentrations.

Animals↗

PubMed1997

Pyelonephritis provokes growth retardation and apoptosis in infant rat renal cortex.

Childhood pyelonephritis is a common cause of renal cortical scarring and hypoplastic kidneys. To understand the mechanisms underlying the cortical lesions, urinary tract infection was induced in three-week-old rats by an intravesical infusion of E. coli, type 06 K13 HL a rat nephropathogenic strain. Four days after infection, histopathological examination showed marked infiltration of leukocytes in the medullary tissue adjoining the calyces and pelvis. In the cortex, signs of inflammation were found only in the cortical zone adjacent to the pelvis. No cells indicative of inflammation were observed in other parts of the cortex. Immunohistochemistry for endogenous proliferating cell nuclear antigen (PCNA) demonstrated a marked decrease in immunoreactivity in proximal tubular (PT) cells. The mitotic response of PT cells, assessed by 3H-thymidine autoradiography, showed a highly significant decrease during the first four days after induction of the infection. Four days after infection, a transient increase in apoptotic cells was observed in cortical cells outside the inflammatory areas. No increase in apoptotic cells was detected in the cortex 10 days after infection. Only a few apoptotic cells were detected in the control kidneys. In conclusion, the data indicate that inhibition of cell proliferation and enhancement of apoptosis may contribute to the renal parenchymal loss after childhood pyelonephritis.

Animals↗

PubMed1997

Inhibition of COMT induces dopamine-dependent natriuresis and inhibition of proximal tubular Na+,K+-ATPase.

The enzyme catechol-O-methyltransferase (COMT), which plays an important role for dopamine metabolism, is abundantly expressed in the kidney. To test whether the natriuretic effects of dopamine may be related to the rate of dopamine metabolism, rats were treated with nitecapone, a peripheral inhibitor of COMT. Nitecapone, given by gavage, induced a highly significant (5.6-fold) increase in sodium excretion, which was associated with an inhibition of the Na+,K+-ATPase activity in both the proximal convoluted and proximal straight tubules (PCT and PST, respectively). These effects were completely abolished if the rats were also treated with a specific dopamine 1 antagonist, SCH 23390. Furthermore, the natriuretic effect of nitecapone was also observed in rats on a high salt diet. The kidney-specific pro-drug to dopamine, glu-dopa, induced a significant, but less pronounced increase in urinary sodium excretion, associated with a dopamine-dependent inhibition of the Na+,K+-ATPase activity in the PCT but not in the PST. Nitecapone and glu-dopa had an additive natriuretic effect. It is concluded that COMT plays an important role in determining the natriuretic effects of the renal dopamine system.

Animals↗

PubMed1997

The natriuretic response to a dopamine DA1 agonist requires endogenous activation of dopamine DA2 receptors.

Dopamine produced in the kidney acts as a natriuretic hormone by inhibiting tubular Na+,K+-ATPase activity. Previous in vitro studies have shown that Na+,K+-ATPase activity in the proximal tubule is inhibited by a synergistic action of dopamine 1 (DA1) and dopamine 2 (DA2) receptors. This in vivo study, performed on rats, investigates whether the natriuretic response to DA requires a synergistic action of DA1 and DA2 receptors. The DA1 agonist, fenoldopam, significantly increased urinary sodium excretion, but there was no increase in sodium excretion when a DA1 agonist was given together with a DA2 antagonist. Neither DA1 nor DA2 antagonists had any influence on sodium excretion. The natriuretic response to fenoldopam was also significantly attenuated after the administration of benserazide, which inhibits aromatic acid decarboxylase and thereby suppresses the endogenous production of dopamine. In conclusion, the natriuretic effect of dopamine depends on the activation of both DA1 and DA2 receptors. The DA2 receptor appears to be constitutively activated by endogenous dopamine.

Animals↗

PubMed1996

Cellular mechanisms for bi-directional regulation of tubular sodium reabsorption.

The molecular mechanisms underlying the regulation of sodium excretion are incompletely known. Here we propose a general model for a bi-directional control of tubular sodium transporters by natriuretic and antinatriuretic factors. The model is based on experimental data from studies on the regulation of the activity of Na+,K+-ATPase, the enzyme that provides the electrochemical gradient necessary for tubular reabsorption of electrolytes and solutes in all tubular segments. Regulation is carried out to a large extent by autocrine and paracrine factors. Of particular interest are the two catecholamines, dopamine and norepinephrine. Dopamine is produced in proximal tubular cells and inhibits Na+,K+-ATPase activity in several tubule segments. Renal dopamine availability is regulated by the degrading enzyme, catechol-O-methyl transferase. Renal sympathetic nerve endings contain norepinephrine and neuropeptide Y (NPY). Activation of alpha-adrenergic receptors increase and activation of beta-adrenergic receptors decrease Na+,K+-ATPase activity. alpha-Adrenergic stimulation increases the Na+ affinity of the enzyme and thereby the driving force for transcellular Na+ transport. NPY acts as a master hormone by synergizing the alpha- and antagonizing the beta-adrenergic effects. Dopamine and norepinephrine control Na+,K+-ATPase activity by exerting opposing forces on a common intracellular signaling system of second messengers, protein kinases and protein phosphatases, ultimately determining the phosphorylation state of Na+,K+-ATPase and thereby its activity. Important crossroads in this network are localized and functionally defined. Phosphorylation sites for protein kinase A and C have been identified and their functional significance has been verified.

Animals↗

PubMed1996

Development of urinary concentrating capacity: role of aquaporin-2.

The capacity to concentrate urine develops progressively during postnatal life in most mammalian species. Here we have examined whether low expression of the arginine vasopressin (AVP)-activated water channel aquaporin-2 (AQP-2) may be a limiting factor for the concentrating capacity in the infant rats. Urine osmolality in response to 24-h dehydration increased significantly from 10 to 40 days of age. The most rapid increase occurred during the weaning period, i.e., days 15-20. A similar developmental pattern was observed for AQP-2 mRNA levels in the renal medulla. AQP-2 protein levels also increased markedly from day 10 to 40. Immunohistochemistry revealed that AQP-2 was exclusively located in collecting duct principal cells both in infant and adult rats but that the signal was much weaker in infants. To further examine the relationship between urinary concentrating capacity and AQP-2 expression, we treated rats with a single injection of betamethasone, which is known to accelerate maturation in several organs. Twenty-four hours after treatment, there was an increase in urine osmolality, renal medullary AQP-2 mRNA, and AQP-2 protein levels in infant but not in adult rats. A single injection of a specific V2 agonist caused within 6 h significant increase of AQP-2 mRNA in both infant and adult. The expression of the mRNA of three other transporters involved in the concentrating process, medullary Na(+)-K(+)-ATPase alpha-subunit, Na-K-2Cl cotransporter, and epithelial chloride channel also increased during the weaning period and were upregulated by glucocorticoids. We conclude that there is a well-synchronized development of the many of the components that determine the concentrating capacity and that the low expression of AQP-2 is one of the limiting factors for low concentrating capacity in infants.

Aging↗

PubMed1994

Endogenous dopamine modulates jejunal sodium absorption during high-salt diet in young but not in adult rats.

BACKGROUND/AIMS: This study was designed to investigate the contribution of endogenous catecholamines to the regulation of small intestinal sodium transport during postnatal development. METHODS: Jejunal permeability was determined by a constant perfusion, nonabsorbable marker technique in weanling, adolescent, and adult rats fed either a high-salt diet or normal-salt diet. Tissue catecholamine levels were determined by high-performance liquid chromatography with electrochemical detection. RESULTS: In 20-day-old but not in 40-day-old rats, a significantly lower net sodium absorption was observed during high-salt diet compared with age-matched controls on normal-salt diet. Inhibition of dopamine synthesis significantly increased the net sodium absorption in 20-day-old rats on high-salt diet compared with untreated 20-day-old rats on high-salt diet. The basal levels of dopamine in 20-day-old rats were twofold higher than in 40-day-old rats. During high-salt diet, both age groups responded with an increase in dopamine production. Norepinephrine levels were significantly higher (30-fold) in 20-day-old rats than in 40-day-old rats, but norepinephrine content was not significantly changed during high-salt diet in either groups. CONCLUSIONS: The results indicate that weanling animals have a greater jejunal sodium absorption than older animals, probably because of higher noradrenergic tonus. A challenge with a high-salt diet results in a decrease of the intestinal sodium absorption in weaning rats but not in adult rats; endogenous dopamine appears to play an important role in this regulation.

Absorption↗

PubMed1994

Increased renal metabolism in diabetes. Mechanism and functional implications.

The coupling between the Na+/glucose cotransporter and Na(+)-K(+)-ATPase (NKA) described for epithelial cells (1) prompted us to study in rats with streptozocin-induced diabetes the effect of increased tubular glucose load on tubular Na+ reabsorption, NKA-dependent O2 consumption (QO2), and NKA activity. Filtered glucose is mainly reabsorbed in the proximal tubuli via the phlorizin-sensitive Na+/glucose cotransporter. In this study, the diabetic rats had a significantly higher renal blood flow (RBF), glomerular filtration rate (GFR), and Na+ reabsorption than the control rats. Total renal QO2 as well as QO2 in cortical tissue, which consists mainly of proximal tubular cells, was significantly higher in diabetic than in control rats. The increase in tissue QO2 was entirely caused by increased NKA-dependent QO2. NKA activity, measured as rate of ATP hydrolysis, was increased in cortical tubular but not glomerular tissue from diabetic rats. Phlorizin treatment abolished the increase in NKA activity, Na+ reabsorption, and QO2, as well as the increase in RBF and GFR in diabetic rats. We conclude that diabetes is associated with increased renal O2 metabolism secondary to the increase in coupled Na+ reabsorption via the Na+/glucose cotransporter and NKA. The increased oxygen consumption might contribute to the hyperperfusion and hyperfiltration in the diabetic kidney.

Adenosine Triphosphate↗

PubMed1993

Bidirectional regulation of Na+,K(+)-ATPase activity by dopamine and an alpha-adrenergic agonist.

Catecholamines have pronounced effects on the renal handling of sodium and water, dopamine-promoting sodium and water excretion, and norepinephrine-promoting sodium and water retention. In the present study, using isolated permeabilized renal tubule cells and intact rats, we have shown that these effects can be attributed to opposing actions of these transmitters on renal tubular Na+,K(+)-ATPase activity. The ability of each of these catecholamines to regulate Na+,K(+)-ATPase activity is affected by the concentration of Na+ as well as by the absence or presence of the opposing catecholamine.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1993

Salt-deficient diet and early weaning inhibit DNA synthesis in immature rat proximal tubular cells.

A maturational gradient exists between the inner and the outer cortical nephrons in infant rats. This study compares the putative growth-retarding effects of early weaning (EW) and a salt-deficient (SD) diet in proximal tubule (PT) cells in the inner and the outer cortex. The mitotic response was measured as tritiated-thymidine incorporation in PT cells from 18- to 22-day-old rats. Under basal conditions the mitotic index is the same in the inner and the outer cortex. EW retarded body growth, but had no significant effect on the kidney/body weight (KW/BW) ratio. EW caused a significant decrease in DNA synthesis in both the outer and the inner cortical PT cells, but the effect was significantly more pronounced in the outer cortex. The SD rats had significantly lower levels of serum sodium, lower urinary sodium excretion, slightly decreased BW, but no differences in KW/BW ratio or in dry/wet KW. SD caused a decrease in DNA synthesis in the PT cells in the outer cortex, but not in the inner cortex. In conclusion, two manipulations that can retard proliferation of PT cells, i.e. EW and a SD diet, have a more pronounced effect in immature than in mature PT cells.

Aging↗

PubMed1993

Dopamine regulation of renal Na+,K(+)-ATPase activity is lacking in Dahl salt-sensitive rats.

Dopamine is a natriuretic hormone that acts by inhibiting tubular Na+, K(+)-ATPase activity by activation of the dopamine-1 receptor (the thick ascending limb [TAL] of Henle) or by a synergistic effect of dopamine-1 and dopamine-2 receptors (the proximal tubule). The dopamine-1 receptor is coupled to adenylate cyclase. In this article we show that prehypertensive Dahl salt-sensitive (DS) rats have a blunted natriuretic response to dopamine determined during euvolemic conditions compared with Dahl salt-resistant (DR) rats. Furthermore, we have examined the renal tubular effects of dopamine in DS and DR rats. Basal Na+,K(+)-ATPase activity was similar in DS and DR rats. In proximal tubule, dopamine (10(-5) M) inhibited Na+,K(+)-ATPase activity in DR but not in DS rats. The dopamine-2 agonist LY171555 (10(-5) M) together with dibutyryl cyclic AMP (10(-6) M) inhibited proximal tubule Na+,K(+)-ATPase activity in both DS and DR rats. LY171555 alone had no effect. In TAL, the dopamine-1 agonist fenoldopam (10(-5) M) inhibited Na+,K(+)-ATPase activity in DR but not in DS rats. Dibutyryl cyclic AMP (10(-5) M) inhibited TAL Na+,K(+)-ATPase activity in both DS and DR rats. In cell suspensions from the cortex and the medulla, activation of the dopamine-1 receptor significantly increased cyclic AMP content in DR but not in DS rats. The results indicate that DS rats lack the capacity to inhibit tubular Na+,K(+)-ATPase activity because of a defective dopamine-1 receptor adenylate cyclase coupling. This defect may contribute to the impaired natriuretic capacity in DS rats.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed1992

Sorbinil does not prevent hyperfiltration, elevated ultrafiltration pressure and albuminuria in streptozotocin-diabetic rats.

The effects of aldose reductase inhibition on kidney function were studied in rats with streptozotocin-induced diabetes mellitus. Diabetic rats were fed sorbinil (20 and 50 mg/kg) by daily gastric gavage and were compared with untreated diabetic rats and normal rats. The rats were under daily supervision with regard to blood glucose control, insulin administration and body weight. The aim was to promote continuous body growth and to maintain the blood glucose concentration at around 22 mmol/l without large day-to-day fluctuations. The renal functional changes observed in this well-established diabetic model closely resembled those reported in human Type 1 (insulin-dependent) diabetes mellitus. Sorbinil treatment completely prevented renal cortical sorbital accumulation, but did not abolish kidney enlargement or the increase in ultrafiltration pressure and glomerular filtration rate. Albumin excretion was increased to the same extent in the sorbinil-treated and in the untreated diabetic rats. We conclude that increased metabolism of glucose to sorbitol does not cause the hyperfiltration in rats with streptozotocin-induced diabetes.

Albuminuria↗

PubMed1992

Calcium supplementation and thyroid hormone protect against gentamicin-induced inhibition of proximal tubular Na+,K(+)-ATPase activity and other renal functional changes.

Gentamicin can cause proximal tubule necrosis. We have shown that inhibition of PT Na+,K(+)-ATPase activity is rapidly induced by gentamicin. We have now investigated whether manipulations known to attenuate the negative effects of gentamicin on renal excretory capacity, i.e. high calcium intake and L-thyroxine treatment, will also attenuate gentamicin-induced inhibition of Na+,K(+)-ATPase activity and ameliorated signs of proximal tubule damage. Rats were gentamicin- or vehicle-treated for 7 days. Sub-groups were given 4% calcium (Ca) supplements or L-thyroxine 20 micrograms 100 g-1 body weight daily. Gentamicin significantly reduced the glomerular filtration rate and increased the urinary excretion of the proximal tubule lysosomal enzyme, N-acetyl-beta-D-glucosaminidase. Gentamicin significantly reduced proximal tubule Na+,K(+)-ATPase activity, measured in single permeabilized proximal tubule segments. Sodium excretion was inversely correlated to proximal tubule Na+,K(+)-ATPase activity. Both calcium and L-thyroxine alleviated all gentamicin-induced side-effects on renal function as well as on proximal tubule Na+,K(+)-ATPase activity. Calcium and L-thyroxine had no significant effect on renal function. L-thyroxine, but not calcium, increased proximal tubule Na+,K(+)-ATPase activity in control rats. Renal cortical tissue gentamicin concentration was not influenced by calcium but was significantly lowered by L-thyroxine. Two procedures which, via different mechanisms, afford protection from gentamicin-induced changes in renal function also give protection from gentamicin-induced inhibition of Na+,K(+)-ATPase activity. This suggests that loss of integrity of the Na+,K(+)-ATPase enzyme contributes to gentamicin-induced nephrotoxicity.

Acetylglucosaminidase↗