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PubMed1982

Regional renal and splanchnic blood flows during nicotine infusion: effects of alpha and of combined alpha and beta adrenergic blockade.

Renal (cortex and medulla) and splanchnic (duodenum, liver, pancreas and spleen) blood flows were measured with 25-mu radioactive microspheres in anesthetized, open-chest dogs. The effects of nicotine (36 micrograms/kg/min i.v.) before and after selective alpha adrenergic blockade (phenoxybenzamine, 1 mg/kg i.v.) and before and after combined alpha and beta adrenergic blockade (phenoxybenzamine, 1 mg/kg i.v. and propranolol, 1 mg/kg i.v.) were evaluated. Before adrenergic blockade, nicotine increased arterial pressure (+82%) but had heterogeneous directional effects on regional blood flows: pancreas (-64%), duodenum (-33%), kidney cortex (-31%), kidney medulla (-17%), liver (+5%) and spleen (+71%). Vascular conductance was reduced in kidney cortex (-61%), kidney medulla (-57%), duodenum (-59%), liver (-46%) and pancreas (-79%) and was not altered in spleen. Selective alpha adrenergic blockade prevented the hypertensive response to nicotine, but heterogeneous changes in regional flows persisted: pancreas (-40%), spleen (-40%), kidney medulla (-35%), kidney cortex (-31%), liver (+50%) and duodenum (+74%). After combined alpha and beta adrenergic blockade, nicotine increased systemic arterial pressure (+75%) and decreased vascular conductance in all tissues. Results indicate: 1) a heterogeneous influence of nicotine in renal and splanchnic circulations associated with regional differences in activities of alpha and beta adrenergic receptors and 2) a potent nonadrenergic vasoconstrictor response in these circulations to nicotine after blockade of alpha and beta adrenergic receptors.

Adrenergic alpha-Antagonists↗
PubMed2001

Identification of the gamma-aminobutyric acid receptor beta(2) and beta(3) subunits in rat, rabbit, and human kidneys.

The properties and functions of gamma-aminobutyric acid (GABA(A)) receptors in the mammalian central nervous system are well studied. However, the presence and significance of GABA(A) receptors in nonneural tissue is less clear. The goal of this study was to examine the expression and localization of the GABA(A) receptor beta(2) and beta(3) subunits in the kidney. Reverse transcriptase products from RNA isolated from rat and rabbit kidney cortex and cerebellum and rabbit S(2) segments were amplified by use of PCR and GABA(A) beta(2) and beta(3) subunit-specific primers. Sequencing of the kidney PCR products revealed that the rat kidney cortex and rat neuronal GABA(A) receptor beta(2) subunit were identical in nucleotide composition. The rabbit kidney and rabbit neuronal GABA(A) receptor beta(2) subunit were 99% identical in nucleotide composition. Sequencing of the kidney PCR products revealed that the rat kidney cortex and rat neuronal GABA(A) receptor beta(3) subunits were 93% and 95% identical in nucleotide and amino acid composition, and rabbit kidney cortex and rabbit neuronal GABA(A) receptor beta(3) subunits were 95% and 98% identical in nucleotide and amino acid composition, respectively. PCR screening of a human kidney cDNA library and sequencing revealed that the human kidney cortex and neuronal beta(3) subunits were identical in nucleotide composition. Immunoblot analysis of rat kidney cortex and brain identified immunoreactive proteins in the 55 to 57 kD region, corresponding to the GABA(A) receptor beta(2) and beta(3) subunits. Immunohistochemistry revealed cytosolic and basolateral staining of the proximal convoluted and straight tubule. These results provide compelling evidence for the expression of the GABA(A) receptor beta(2) and beta(3) subunits in the kidney of multiple species and the localization of the beta(2)/beta(3) subunits to the renal proximal tubule.

Amino Acid Sequence↗
PubMed1996

The relaxivity of Gd-EOB-DTPA and Gd-DTPA in liver and kidney of the Wistar rat.

The NMR relaxivities of Gd-EOB-DTPA and Gd-DTPA were determined in the kidney and liver of intact male Wistar rats immediately following sacrifice and in vitro in solutions and gels, at 1.5 T using a clinical MR scanner, T1 and T2 values of tissue samples were derived from spin-echo image sequences. Tissue gadolinium concentrations were determined by radioassay of Gd153, Gd-EOB-DTPA T1 and T2 relaxivities, R1 and R2 (s-1 mmole-1 kg), were found to be 10.7 +/- 0.5 and 22.5 +/- 3.2 respectively, for liver, 2.4 +/- 0.2 and 12.1 +/- 1.7 for kidney cortex, 2.7 +/- 0.2 and 14.5 +/- 1.9 for kidney outer medulla, 2.0 +/- 0.2 and 11.4 +/- 2.1 for kidney inner medulla. Gd-DTPA R1 and R2 were found to be 4.8 +/- 0.4 and 14.5 +/- 3.7 for liver, 1.2 +/- 0.1 and 7.9 +/- 0.8 for kidney cortex, 1.6 +/- 0.1 and 10.2 +/- 1.4 for kidney outer medulla, 1.3 +/- 0.1 and 10.2 +/- 1.2 for kidney inner medulla. Gd-EOB-DTPA and Gd-DTPA R1 was increased in liver compared to agarose gets at 38 degrees C (4.49 +/- 0.03 and 3.47 +/- 0.06), but reduced in kidney tissues. All R2 were elevated compared to agarose gels at 38 degrees C (5.72 +/- 0.12 and 4.12 +/- 0.03). Elevated R2 and R1 (expressed in terms of the concentration of gadolinium per kg of tissue) can be accounted for in part by the lower water content of tissues compared with gels or solutions increased microviscosity and binding to macromolecules. In addition, susceptibility effects may give rise to further increases in R2. By contrast, the reduced R1 observed in kidney may be the result of compartmentalization of the magnetopharmaceuticals. Statistically improved fits were obtained for T1 recovery curves for liver in the presence of Gd-EOB-DTPA when a dual exponential model was used. Assuming in vitro values for the relaxivities of these artificial contrast agents will lead to inaccuracies when relating observed signal enhancement factors to tissue gadolinium concentration.

Animals↗
PubMed1996

Pharmacokinetics, tissue distribution, and expression efficiency of plasmid [33P]DNA following intravenous administration of DNA/cationic lipid complexes in mice: use of a novel radionuclide approach.

The pharmacokinetics, tissue distribution, and efficacy of a systemic gene transfer method were examined in male BALB/c mice (6-8 weeks old) using 33P-labeled plasmid DNA for luciferase. The DNA was delivered via tail vein injection in saline ([33P]DNA) or in a cationic lipid formulation ([33P]DNA/lipid). One group of mice received approximately equal to 1-3 microCi (45 micrograms of DNA) of either formulation, and mice were euthanized at 2 and 20 min, and 1 and 24 h postdose (2 mice/time point). Blood and plasma radioactivity were quantified, and whole body autoradiographic (WBAR) images were obtained from 20-microns whole body sections. A tissue distribution (TD) study was conducted in a second group of mice, which received approximately equal to 4-6 microCi (45-60 micrograms of DNA) of [33P]DNA/lipid. Mice were euthanized at 1.5 h (1 mouse; [33P]DNA/lipid) or 24 h (2 mice/ group), and organ radioactivity and luciferase expression were measured in lung, liver, kidney, spleen thymus, and parotid salivary gland by direct quantitation methods. Microautoradiography (MAR) was performed on a third group of mice (n = 2), which received 3 microCi (45 micrograms of DNA) of [33P]DNA/lipid and were euthanized at 24 h postdose. For WBAR, the [33P]DNA/lipid tissue distribution (% dose equiv/g) at 2 min was lung >> liver > spleen (red pulp) > kidney (cortex); at 24 h the ranking was spleen (red pulp) > liver > lung, kidney (cortex). The [33P]DNA organ distribution observed at 2 min was liver >> spleen (red pulp) > lung, blood > kidney (cortex); at 24 h the ranking was liver, spleen (red pulp) > kidney (cortex) > lung, blood. High levels of radioactivity in bone (cortical, marrow, growth plate) in both groups may represent uptake of the 33P-labeled test articles by the cellular component of the bone marrow, particularly macrophages, as well as deposition of [33P]phosphate in the bone matrix following metabolism of the [33P]DNA. In the luciferase component of the study, no expression was observed in the [33P]DNA group at 24 h. The [33P]- DNA/lip group exhibited expression as early as 1.5 h in the lung; at 24 h, expression was seen in all the organs examined. Microautoradiography of 24-h tissue samples revealed radioactivity in hepatic Kupffer cells, reticuloendothelial system cells in the marginal zone of the spleen, and diffusely along alveolar septae with scattered accumulations in alveolar macrophages. The results of the WBAR, TD, MAR, and luciferase assay show that the use of cationic lipids significantly altered the biodistribution and resulting expression of the DNA plasmid. Further, 33P (0.25 MeV beta, half-life = 25 days) was shown to be an excellent radionuclide for quantitative WBA and MAR, providing sharp images with less personal hazard and greater ease of handling than 32P (1.71 MeV beta, half-life = 14.3 days).

Animals↗
PubMed1970

Ketone body and fatty acid metabolism in sheep tissues. 3-Hydroxybutyrate dehydrogenase, a cytoplasmic enzyme in sheep liver and kidney.

1. 3-Hydroxybutyrate dehydrogenase (EC 1.1.1.30) activities in sheep kidney cortex, rumen epithelium, skeletal muscle, brain, heart and liver were 177, 41, 38, 33, 27 and 17mumol/h per g of tissue respectively, and in rat liver and kidney cortex the values were 1150 and 170 respectively. 2. In sheep liver and kidney cortex the 3-hydroxybutyrate dehydrogenase was located predominantly in the cytosol fractions. In contrast, the enzyme was found in the mitochondria in rat liver and kidney cortex. 3. Laurate, myristate, palmitate and stearate were not oxidized by sheep liver mitochondria, whereas the l-carnitine esters were oxidized at appreciable rates. The free acids were readily oxidized by rat liver mitochondria. 4. During oxidation of palmitoyl-l-carnitine by sheep liver mitochondria, acetoacetate production accounted for 63% of the oxygen uptake. No 3-hydroxybutyrate was formed, even after 10min anaerobic incubation, except when sheep liver cytosol was added. With rat liver mitochondria, half of the preformed acetoacetate was converted into 3-hydroxybutyrate after anaerobic incubation. 5. Measurement of ketone bodies by using specific enzymic methods (Williamson, Mellanby & Krebs, 1962) showed that blood of normal sheep and cattle has a high [3-hydroxybutyrate]/[acetoacetate] ratio, in contrast with that of non-ruminants (rats and pigeons). This ratio in the blood of lambs was similar to that of non-ruminants. The ratio in sheep blood decreased on starvation and rose again on re-feeding. 6. The physiological implications of the low activity of 3-hydroxybutyrate dehydrogenase in sheep liver and the fact that it is found in the cytoplasm in sheep liver and kidney cortex are discussed.

Acetoacetates↗
PubMed2002

Correlations of trace element levels within and between different normal autopsy tissues analyzed by inductively coupled plasma atomic emission spectrometry (ICP-AES).

Imbalance in trace metal metabolism may lead to metal interactions that may be of patho-physiological importance. Knowledge of the relation between trace metals in normal tissues is needed to assess abnormal deviations associated with disease. In this study correlations between Cu, Co, Cr, Fe, Mn, Ni, Se, Zn, Al, Ba, Cd, Pb and Sr within the same and between 6 different, normal autopsy tissues were determined using Spearman rank correlation analysis based on analytical data obtained by inductively coupled plasma atomic emission spectrometry (ICP-AES). Fe-Co were correlated in most tissues. Cu-Mn, Zn-Cu, Zn-Mn and Zn-Cd were highly correlated in the kidney medulla. Ni-Ni, Sr-Sr and Cd-Cd were correlated between several tissues, while Fe-Fe, Zn-Zn and Cu-Cu were correlated between kidney cortex and medulla. Mn-Mn was highly correlated between the liver and brain front lobe, cerebellum and heart. High correlations were found for Ni-Co and for Se-Mn between the kidney cortex and brain front lobe and pancreas respectively. Inverse correlations were found for Se-Cd between kidney cortex and cerebellum, for Se-Cd and Cd-Zn between kidney medulla and heart, for Co-Sr and Fe-Sr between the liver and kidney cortex and heart respectively, and for Sr-Mn between kidney medulla and pancreas. A large number of trace elements are statistically correlated within and between different, normal tissues. Knowledge of these correlations may contribute to increase the understanding of kinetic interactions of trace metals in the body and the role of such interactions in normal and disturbed trace metal metabolism.

Adolescent↗
PubMed1989

Tissue-specific differential modulation of arginase and ornithine aminotransferase by hydrocortisone during various developmental stages of the rat.

The activities and regulatory patterns of arginase and ornithine aminotransferase (OAT) of the liver (a mitotic tissue) and kidney cortex (a post-mitotic tissue) of immature, adult, and senescent male rats were studied. The activities of the liver enzymes were highest in the immature rat and decreased gradually with age. However, in the kidney cortex, the activity of arginase was highest and decreased significantly thereafter while that of OAT shows no significant change throughout the life span of the rat. Further, the activity of kidney cortex arginase was approximately 1/20th of that of the liver enzyme. Adrenalectomy and hydrocortisone treatments altered the activity of arginase in both tissues and that of OAT in the liver only. However, the kidney cortex OAT was not responsive towards these treatments. Actinomycin D inhibited the hydrocortisone-mediated induction of arginase of both the liver and kidney cortex and that of the liver OAT.

Adrenalectomy↗
PubMedDate not supplied

Preliminary study of the distribution of the toxic elements As, Cd, and Hg in human hair and tissues by RNAA.

In order to study the relationships between trace element concentrations of hair and internal body burdens, a radiochemical NAA technique has been used for determination of the elements As, Cd, and Hg in autopsy samples of liver, kidney-cortex, lung, and hair from 24 male persons who died by accident. High significant positive correlations were observed between the As concentration in hair and in kidney-cortex, and between Cd and Zn concentrations in kidney-cortex. The contents of Cd, both for lung and kidney-cortex, were related to the smoking habits of the subjects.

Adult↗
PubMed1993

Functional expression of cAMP-dependent and independent urea transporters in Xenopus oocytes.

Facilitated transport of urea by the inner medullary collecting duct in kidney is important for the urinary concentrating mechanism. To examine the nature and tissue distribution of urea transporters, mRNA was isolated from different tissues and expressed in Xenopus oocytes. [14C]urea and [3H]methylglucose uptake were measured at 21 degrees C at 64 h after microinjection of mRNA. Relative urea uptake in oocytes injected with 50 ng of unfractionated mRNA was (n = 6-42): 1.0 (water-injected control), 1.0 +/- 0.3 (human kidney cortex), 2.9 +/- 0.5 (rat kidney papilla), 2.5 +/- 0.5 (human kidney papilla), 2.7 +/- 0.3 (rat liver), 1.1 +/- 0.3 (rat brain), 1.2 +/- 0.3 (rat muscle), and 2.6 +/- 0.3 (rabbit reticulocyte). Urea uptake was inhibited to near control values by 0.2 mM phloretin and 0.2 mM p-chloromercuribenzenesulfonate (pCMBS) in oocytes injected with mRNA from kidney medulla, liver, and reticulocyte; phloretin and pCMBS had no effect in control oocytes and oocytes injected with mRNA from kidney cortex, brain, and muscle. Urea uptake was strongly increased in oocytes injected with kidney medulla mRNA (4.4-fold over control) by a 5-min preincubation with the adenosine 3',5'-cyclic monophosphate (cAMP) agonist adenosine-3',5'-cyclic monophosphorothioate (Sp-cAMPS) or a mixture of CPT-cAMP, forskolin, and 3-isobutyl-1-methylxanthine; cAMP agonists did not affect urea uptake in oocytes expressing the reticulocyte and liver urea transporters. As an internal control, (phloretin inhibitable) glucose uptake was enhanced in all oocytes (up to 5-fold greater than control), and was not affected by pCMBS and the cAMP agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1969

Effects of added nucleotides on renal carbohydrate metabolism.

1. The regulatory effects that adenine nucleotides are known to exert on enzymes of glycolysis and gluconeogenesis were demonstrated to operate in kidney-cortex slices and in the isolated perfused rat kidney by the addition of exogenous ATP, ADP and AMP to the incubation or perfusion media. 2. Both preparations rapidly converted added ATP into ADP and AMP, and ADP into AMP; added AMP was rapidly dephosphorylated. AMP formed from ATP was dephosphorylated at a lower rate than was added AMP, especially when the initial ATP concentration was high (10mm). Deamination of added AMP occurred more slowly than dephosphorylation of AMP. 3. Gluconeogenesis from lactate or propionate by rat kidney-cortex slices, and from lactate by the isolated perfused rat kidney, was inhibited by the addition of adenine nucleotides to the incubation or perfusion media. In contrast, oxygen consumption and the utilization of propionate or lactate by slices were not significantly affected by added ATP or AMP. 4. The extent and rapidity of onset of the inhibition of renal gluconeogenesis were proportional to the AMP concentration in the medium and the tissue, and were not due to the production of acid or P(i) or the formation of complexes with Mg(2+) ions. 5. Glucose uptake by kidney-cortex slices was stimulated 30-50% by added ATP, but the extra glucose removed was not oxidized to carbon dioxide and did not all appear as lactate. Glucose uptake, but not lactate production, by the isolated perfused kidney was also stimulated by the addition of ATP or AMP. 6. In the presence of either glucose or lactate, ATP and AMP greatly increased the concentrations of C(3) phosphorylated intermediates and fructose 1,6-diphosphate in the kidney. There was a simultaneous rise in the concentration of malate and fall in the concentration of alpha-oxoglutarate. 7. The effects of added adenine nucleotides on renal carbohydrate metabolism seem to be mainly due to an increased concentration of intracellular AMP, which inhibits fructose diphosphatase and deinhibits phosphofructokinase. This conclusion is supported by the accumulation of intermediates of the glycolytic pathway between fructose diphosphate and pyruvate. 8. ATP or ADP (10mm) added to the medium perfusing an isolated rat kidney temporarily increased the renal vascular resistance, greatly diminishing the flow rate of perfusion medium for a period of several minutes.

Adenine Nucleotides↗
PubMed1976

Studies on (Na+ plus K+)-activated ATPase. XXXVII. Stabilization by cations of the enzyme-ouabain complex formed with Mg1+ and inorganic phosphate.

Dissociation of the (Na+ + K+)-ATPase ouabain complex, formed in the presence of Mg2+ and inorganic phosphate (Complex II), is inhibited by Mg2+ (21-45%) and the alkali cations Na+ (25-59%) and K+ (27-75%) when kidney cortex tissue (bovine, rabbit, guinea pig) is the enzyme source. Choline chloride at 200 mM, equivalent to the highest concentration of NaCl tested, does not inhibit. Dissociation of Complex II from brain cortex (bovine, rat, rabbit) or heart muscle (rabbit) is much less inhibited: 0-11% by Na+ and 11-19% by K+. The degree of inhibition is not directly related to the size of the dissociation rate constant (k-) of the various complexes, but rather to the extent of interaction between the cation and ouabain binding sites for these tissues. Inhibition curves for Na+ and K+ are sigmoidal. Half-maximal inhibition for rabbit brain and kidney cortex is at 30-40 mM Na+ and 6-10 mM K+, and the maximally inhibitory concentrations are 50-150 and 15-20 mM, respectively. Maximal inhibition by Na+ or K+ for these tissues is the same. For guinea pig kidney cortex Na+ and K+ are almost equally effective, but 150 mM K+ or 200 mM Na+ are still not saturating, and inhibition curves indicate high- and low-affinity binding sites for the alkali cations. The inhibition curve for Mg2+ is not sigmoidal. In the kidney preparations Mg2+ inhibits half-maximally at 0.4-0.5 mM, maximally at 1-3 mM. Maximal inhibition by Mg2+ is higher than by Na+ or K+ for rabbit kidney cortex and lower for guinea pig kidney cortex. There is no competition or additivity among the cations, indicating the existence of different binding sites for Mg2+ and the alkali cations. Complex II differs in stability in the extent of inhibition, in the dependence of inhibition on the cation concentration and in the absence of antagonism between Na+ and K+, from the ouabain complex formed via phosphorylation by ATP (Complex I). This indicates that the phosphorylation states for the complexes are clearly different.

Adenosine Triphosphatases↗
PubMed1996

Isolation and characterisation of the class alpha, mu and pi glutathione transferases in LLC-PK1 and pig kidney.

Glutathione S-transferase (GST) isoenzymes from pig kidney cortex and LLC-PK1 (an established cell line derived from the pig proximal tubule) were purified by affinity chromatography, anionic and cationic chromatofocusing. Purification revealed nine isoenzymes in the pig kidney cortex and five isoenzymes in the LLC-PK1 cell line. SDS-polyacrylamide gel electrophoresis showed that the pig kidney cortex isoenzymes were homo- or heterodimeric; LLC-PK1 isoenzymes, however, were homodimeric. Isoenzymes from pig and LLC-PK1 showed a higher affinity towards glutathione. The isoenzymes were further characterised and divided into the different GST classes by studying specific inhibitors, specific substrates and immunological properties. Pig GSTs belong to class alpha, mu and pi. The GSTs in LLC-PK1 cells, on the other hand, belong to class pi and mu. The isoenzyme pattern in LLC-PK1 cells indicates the dedifferentiation of this particular cell line compared with the pig kidney cortex.

Animals↗
PubMed1988

The effect of aldose reductase inhibitor Statil (ICI 128436) on the glucose over-utilization in kidney of diabetic rats.

The present study examined the effect of the aldose reductase inhibitor Statil (ICI 128436, ICI, Cheshire, U.K.) on the levels of metabolites and activities of enzymes involved in the glycolysis, polyol pathway and pentose phosphate pathway and on the flux of radioactive glucose through these pathways in kidney of streptozotocin diabetic rats. In kidneys of diabetic rats of 30 days duration the level of sorbitol was increased by +82% and fructose concentration was raised by +42%. After treatment with Statil for 9 days (reversal study) a significant fall in kidney sorbitol concentration and kidney fructose concentration was found. Lactate and UDP-glucose concentrations which were both significantly raised in diabetes by +80% and +23% respectively decreased by 20% after Statil treatment, together with a decline in UDP-glucose dehydrogenase activity. Aldose reductase and sorbitol dehydrogenase activities were also significantly lowered by Statil. In the reversal study there was no significant effect of Statil on the flux of glucose via alternative routes in the kidney cortex. In kidneys of diabetic rats of 9 days duration, the level of sorbitol increased by +61% and the concentration of fructose was raised by +30%. The treatment with Statil (25 mg/kg) from the day of induction of diabetes (prevention study) prevented the accumulation of sorbitol, fructose and UDP-glucose. The increase in the incorporation of radioactive glucose through the pentose phosphate pathway seen in diabetes was less marked in the renal cortex of diabetic rats treated with Statil ab initio.

Animals↗
PubMed1978

Covalent binding of metabolites of acetaminophen to kidney protein and depletion of renal glutathione.

Experiments in CD-1 mice and Sprague-Dawley rats were carried out to determine the extent to which biochemical changes described previously for acute acetaminophen-induced hepatotoxicity might be applicable to the kidney. After intraperitoneal injection of acetaminophen, tissue glutathione and covalent binding of tritiated metabolites of acetaminophen to tissue protein were measured for liver, kidney cortex and kidney papilla. Glutathione was reduced more in mice than in rats, and more in liver than in kidney, without appearance of oxidized glutathione in either tissue. Covalent binding was likewise greater in mice than in rats and greater in liver than in kidney. The determination of covalent binding was extremely sensitive to the trace radiochemical impurities of the labeled drug. With prior administration of 3-methyl-cholanthrene, the induced changes were far greater in liver than in kidney, suggesting that the formation of a reactive metabolite from acetaminophen occurred in each organ by slightly different mechanisms. At doses less than those associated with demonstrable acute toxicity, the duration of covalent binding to protein was longer for renal papilla than for renal cortex or for liver. The results may be applicable to the pathogenesis of both acute and chronic nephrotoxicity.

Acetaminophen↗
PubMed1994

Endothelin receptor subtypes A and B are up-regulated in an experimental model of acute renal failure.

The two endothelin (ET) receptor subtypes (ETA and ETB) have been characterized in rat kidney from normal rats and rats with acute renal failure induced by hypertonic glycerol administration. In control rats, the total number of ET receptors in kidney cortex and medulla was 155 and 386 fmol/mg of protein, respectively. The ratio of ETA to ETB receptors was 54:46 in renal cortex and 35:65 in renal medulla. Treatment of rats with 10 ml/kg glycerol (50%, w/v) intramuscularly resulted in severe renal dysfunction; the serum urea concentration increased from 0.46 to 2.65 g/liter and the creatinine clearance decreased from 1.06 to 0.30 ml/min. Ligand binding studies showed that glycerol-induced acute renal failure was associated with a marked up-regulation of ETA and ETB receptor subtypes in both cortex and medulla. In glycerol-treated rats, the total ET receptor density in kidney cortex and medulla was increased to 294 and 1172 fmol/mg of protein, with ETA/ETB ratios of 52:48 and 31:69, respectively. The upregulatory effect of glycerol treatment was significantly more pronounced in renal medulla than renal cortex and affected ETB receptors preferentially, compared with ETA receptors. Subsequently, ETA and ETB receptor mRNA levels were markedly increased by glycerol administration in both kidney cortex and medulla, as assessed by polymerase chain reaction coupled to reverse transcription. These results suggest that up-regulation of renal ET receptors, particularly ETB receptors in kidney medulla, may account for or contribute to renal function impairment induced by glycerol, and they support a pathophysiological role for ET in acute renal failure.

Acute Kidney Injury↗
PubMed2005

Serum thymic factor, FTS, attenuates cisplatin nephrotoxicity by suppressing cisplatin-induced ERK activation.

Serum thymic factor (FTS), a thymic peptide hormone, has been reported to attenuate the bleomycin-induced pulmonary injury and also experimental pancreatitis and diabetes. In the present study, we investigated the effect of FTS on cis-diamminedichloroplatinum II (cisplatin)-induced nephrotoxicity. We have already demonstrated that cephaloridine, a nephrotoxic antibiotic, leads to extracellular signal-regulated protein kinase (ERK) activation in the rat kidney, which probably contributes to cephaloridine-induced renal dysfunction. The aim of this study was to examine the effect of cisplatin on ERK activation in the rat kidney and also the effect of FTS on cisplatin-induced nephrotoxicity in rats. In vitro treatment of LLC-PK1 cells with FTS significantly ameliorated cisplatin-induced cell injury. Treatment of rats with intravenous cisplatin for 3 days markedly induced renal dysfunction and increased platinum contents in the kidney cortex. An increase in pERK was detected in the nuclear fraction prepared from the rat kidney cortex from days 1 to 3 after injection of cisplatin. FTS suppressed cisplatin-induced renal dysfunction and ERK activation in the kidney. FTS did not influence any Pt contents in the kidney after cisplatin administration. FTS has been shown to enhance the in vivo expression of heat shock protein (HSP) 70 in the kidney cortex. The beneficial role of FTS against cisplatin nephrotoxicity may be mediated in part by HSP70, as suggested by its up-regulation in the kidney cortex treated with FTS alone. Our results suggest that FTS participates in protection from cisplatin-induced nephrotoxicity by suppressing ERK activation caused by cisplatin.

Animals↗
PubMed1988

Thyroidal regulation of rat renal and hepatic Na,K-ATPase gene expression.

Na,K-ATPase activity, Na,K-ATPase alpha- and beta-subunit mRNA abundance (mRNA alpha and mRNA beta), and gene transcription rates were determined in kidney cortex and liver of hypothyroid and triiodothyronine (T3)-treated rats. In hypothyroid rats, Na,K-ATPase activity (expressed per unit of DNA) was 3.6-fold greater in kidney cortex than liver, and the abundance of mRNA alpha and mRNA beta in kidney cortex exceeded that of liver by 2.8- and 5.2-fold, respectively. In vitro nuclear run-on analysis revealed similar rates of Na,K-ATPase alpha and beta gene transcription in nuclei isolated from either kidney cortex or liver. Administration of T3 for 72 h elicited a 2.3-fold stimulation of renal Na,K-ATPase activity that was associated with a 3.1- and 2.6-fold increase of mRNA alpha and mRNA beta content, respectively. In contrast, T3 induced a 1.3-fold stimulation of liver Na,K-ATPase activity accompanied by a 7.3-fold increase in mRNA alpha and no change in mRNA beta abundance. Transcription rates of alpha and beta genes (assayed by nuclear run-on) in renal cortex were both stimulated 1.8-fold in response to T3 injection. Similarly in liver nuclei, T3 treatment produced a 1.4- and 1.3-fold stimulation in the rate of alpha and beta gene transcription, respectively. These results indicate that significant discrepancies exist in the quantitative relationships between control and T3-induced changes in renal and hepatic enzyme activity, mRNA abundance and rate of gene transcription, and imply that the T3-induced increase in Na,K-ATPase abundance is mediated at both transcriptional and post-transcriptional steps.

Actins↗