Proximal tubules

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Administration of atrial natriuretic factor inhibits sodium coupled transport in proximal tubules

Administration of atrial natriuretic factor inhibits sodium coupled transport in proximal tubules

cotransported with Na+ in the proximal tubules of rats. Synthetic ANF peptide consisting of 26 amino acids, 4 micrograms/kg body wt/h, or vehicle in controls, was infused to surgically thyroparathyroidectomized anesthetized rats. After determination of the fractional excretion (FE) of electrolytes (Na+, K+, Pi, Ca2+, Mg2+, HCO3), the kidneys were removed and luminal brush border membrane vesicles (BBMVs) were prepared from renal cortex. Solute transport was measured in BBMVs by rapid filtration techniques. Infusion of ANF peptide increased FENa, FEPi, and FEHCO3; but FECa, FEK, and FEMg were not changed. The increase in FENa was significantly correlated, on the one hand, with increase of FEPi (r = 0.9, n = 7; P less than 0.01) and with increase of FEHCO3 (r = 0.89, n = 7; P less than 0.01). On the other hand, FENa did not correlate with FEK, FECa, or with FEMg. The Na+
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Renin and renin mRNA in proximal tubules of the rat kidney

Renin and renin mRNA in proximal tubules of the rat kidney

The present study was undertaken to assess the presence of renin enzymatic activity and renin mRNA in proximal tubules of rat kidneys, and to determine the effect of converting enzyme inhibition (CEI) on proximal tubule renin gene expression. Proximal convoluted tubules (PCT), proximal straight tubules (PST), outer medullary collecting ducts (OMCD), and glomeruli (Gloms) were isolated by microdissection. Renin activity was measured in sonicated segments by radioimmunoassay. Renin mRNA levels were assessed using a quantitative PCR. Renin activity in PCT averaged 51 +/- 15 microGU/mm compared to 405 +/- 120 microGU/glomerulus. No measurable renin activity was found in PST and OMCD. Renin activity in both glomeruli and tubules had the same pH optimum, between 7.0 and 7.5. Renin mRNA was consistently detectable in cDNA prepared from PCT and PST, although its abundance per mm tubule was about 1/500th that found in one glomerulus. Renin mRNA was not detectable in OMCD. Tubular renin PCR product identity was confirmed by restriction digestion. CEI administration increased glomerular renin activity and renin mRNA, but not proximal tubular renin. The absence of a stimulatory effect of CEI on proximal tubule renin gene expression suggests the operation of different intracellular signals in control of renin synthesis in the proximal tubule than in the vascular compartment.
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Relationship between Para aminohippurate Secretion and Cellular Morphology in Rabbit Proximal Tubules

Relationship between Para aminohippurate Secretion and Cellular Morphology in Rabbit Proximal Tubules

aminohippurate (PAH) secretion is ~threefold greater in the straight segment, or pars recta, than in the convoluted segment, or pars convoluta. However, the possibility that the site of maximal PAH secretion might be related better to particular tubule segments as identified by cell type had not been explored. In addition, the presence or absence of differences in PAH secretion between morphologically identical regions of superficial (SF) vs. juxtamedullary (JM) proximal tubules has not been examined. These issues were studied using a

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Characteristics of salt and water transport in superficial and juxtamedullary straight segments of proximal tubules

Characteristics of salt and water transport in superficial and juxtamedullary straight segments of proximal tubules

The purpose of the present studies was to characterize the nature of salt and water transport out of the superficial (SF) and juxtamedullary (JM) straight segments of rabbit proximal tubules as examined by in vitro microperfusion techniques. When the perfusate consisted of a solution simulating ultrafiltrate of plasma, there were no differences between SF and JM straight tubules in either net reabsorption of fluid (SF=0.47 nl/mm per min; JM=0.56 nl/mm per min) or in transtubular potential difference (PD) (SF=-2.1 mV; JM=-1.8 mV). Removal of glucose and alanine from the perfusate had no effect on the magnitude of the PD in either straight segment. Ouabain decreased both the net reabsorptive rates and the PD. Isosmolal replacement of NaCL by Na-cyclamate (a presumed impermeant anion) in the perfusate and the bath caused an increase in luminal negativity in both segments wheras similar
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The archaeal Dps nanocage targets kidney proximal tubules via glomerular filtration

The archaeal Dps nanocage targets kidney proximal tubules via glomerular filtration

catalysis. These cage-like proteins are of immense importance in nanomedicine due to their propensity to self-assemble from simple identical building blocks to highly ordered architecture and the design flexibility afforded by protein engineering. However, delivery of protein nanocages to the renal tubules remains a major challenge because of the glomerular filtration barrier, which effectively excludes conventional size nanocages. Here, we show that DNA-binding protein from starved cells (Dps) — the extremely small archaeal antioxidant nanocage — is able to cross the glomerular filtration barrier and is endocytosed by the renal proximal tubules. Using a model of endotoxemia, we present an example of the way in which proximal tubule–selective Dps nanocages can limit the degree of endotoxin-induced kidney injury. This was accomplished by amplifying the endogenous antioxidant property of Dps with addition of a dinuclear manganese cluster. Dps is the first-in- class protein cage nanoparticle that can be targeted to renal proximal tubules through glomerular filtration. In addition to its therapeutic potential, chemical and genetic engineering of Dps will offer a nanoplatform to advance our understanding of the physiology and pathophysiology of glomerular filtration and tubular endocytosis.
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Evidence for beta adrenoceptors in proximal tubules  Isoproterenol sensitive adenylate cyclase in pars recta of canine nephron

Evidence for beta adrenoceptors in proximal tubules Isoproterenol sensitive adenylate cyclase in pars recta of canine nephron

Observations in vivo suggest that catecholamines modulate reabsorptive functions of proximal tubules by acting on beta-adrenoceptors. However, beta-catecholamine binding sites or beta-adrenoceptor-sensitive adenylate cyclase (AdC) has not been found in segments of proximal tubules of rat, rabbit, or mouse kidney. In the present study, we investigated the responsiveness of AdC to catecholamines, [8-Arg]vasopressin (AVP), and to parathyroid hormone (PTH) in proximal convoluted tubules (PCT), proximal straight tubules (PST), and in late distal convoluted tubules (LDCT) microdissected from canine kidney. Isoproterenol (ISO) caused a marked and dose-dependent stimulation of AdC in PST (maximum: delta + 850%; half maximum stimulation at 10(-7) M ISO), but ISO had no effect on AdC in PCT. The AdC in both PCT and PST was markedly stimulated by PTH; AVP stimulated the AdC in LDCT but not in PST or in PCT. The stimulatory effect of 10(-5) M ISO in PST (delta + 725%) was significantly greater than in LDCT (delta + 307%);
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Activation of potassium channels contributes to hypoxic injury in proximal tubules

Activation of potassium channels contributes to hypoxic injury in proximal tubules

The mechanisms responsible for the loss of cell potassium during renal ischemia are poorly understood. The present studies examined the hypothesis that potassium channels are activated as an early response to hypoxia and contribute to potassium loss independent from an inhibition of active K+ uptake. Potassium flux in suspensions of freshly isolated rat proximal tubules was measured using an ion-selective electrode. Exposure of the tubules to hypoxia for only 2.5 min resulted in a rise in the passive leak rate of K+ but no decrease in active K+ uptake. The passive leak of K+ was associated with a 40% decrease in cell ATP content. The passive K+ efflux was inhibited by 5 mM Ba2+ (95%) and by 15 mM
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Role of cytosolic calcium independent plasmalogen selective phospholipase A2 in hypoxic injury to rabbit proximal tubules

Role of cytosolic calcium independent plasmalogen selective phospholipase A2 in hypoxic injury to rabbit proximal tubules

diacylglycerophospholipid substrates during hypoxia in rabbit proximal tubules and examined whether inhibition of calcium-independent PLA2 activity is associated with a cytoprotective effect. Subjecting rabbit proximal tubules to hypoxia for 5 min resulted in at least a threefold increase in cytosolic calcium-independent PLA2, which was selective for plasmalogen substrates (control 444 +/- 69 vs hypoxia 1,675 +/- 194 pmol.mg protein-1.min- 1, n = 5). In contrast, no changes in PLA2 activity were observed in the presence of 4 mM EGTA in the membrane fraction using plasmenylcholine substrates. 20 min of hypoxia resulted in an increase in arachidonate from 3 +/- 1 to 28 +/- 4 ng/mg protein and lactate dehydrogenase release from 7.5 +/- 2% to 38 +/- 5%, n = 4. Pretreatment of proximal tubules with 10 microM Compound I, a specific inhibitor of calcium-independent PLA2, resulted in reduction in the magnitude of both hypoxia-induced arachidonic acid release (11 +/- 3 ng/mg protein) and lactate dehydrogenase release (18 +/- 4%). Our data indicate that a significant fraction of PLA2 activity in the proximal […]
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Intracellular glutathione in the protection from anoxic injury in renal proximal tubules

Intracellular glutathione in the protection from anoxic injury in renal proximal tubules

subjected to 40 min of anoxia and 40 min of reoxygenation. Low GSH tubules were protected from plasma membrane damage during anoxia by exogenous addition of 1 mM GSH or GLY, reducing lactate dehydrogenase (LDH) release from 42 +/- 7 to 14 +/- 1 and 10 +/- 1%, respectively. High GSH tubules were equally protected from anoxic damage without exogenous additions. Since the high GSH content approximates the in vivo values, it may be concluded that GSH may be cytoprotective during anoxia in vivo. However, it is not the intracellular GSH itself that is cytoprotective; rather, this protection resides in the ability to produce GLY, which appears to be the cytoprotective agent. Alanine was also shown to have similar cytoprotective properties, although higher concentrations were required. Sulfhydryl reducing agents such as cysteine and dithiothreitol offered less, but significant protection from anoxic damage. Protection by GSH, GLY, or alanine was not associated […]
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Micropuncture study of the effect of various diuretics on sodium reabsorption by the proximal tubules of the dog

Micropuncture study of the effect of various diuretics on sodium reabsorption by the proximal tubules of the dog

Acute saline infusion, however, markedly depressed sodium reabsorption by the proximal tubule, an effect that was independent of changes in glomerular filtration rate and occurred in the[r]

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Isovolumetric regulation of isolated S2 proximal tubules in anisotonic media

Isovolumetric regulation of isolated S2 proximal tubules in anisotonic media

gradually changed over a range from 110 to 480 mosM. At 1.5 mosM/min, cell volume remained constant between 167 +/- 9 and 361 +/- 7 mosM, a phenomenon termed isovolumetric regulation (IVR). Cells lost intracellular solutes in hypotonic and gained intracellular solutes in hypertonic media. Raffinose or choline chloride substitution showed that osmolality, rather than NaCl, signalled cell volume maintenance in hyperosmotic media. Cooling (7-10 degrees C) blocked IVR. IVR was maintained when osmolality was lowered at a rate of 27, but not at 42 mosM/min. IVR was not observed when the rate of osmolality increase exceeded 3 mosM/min. We conclude that proximal tubule cells
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Intrarenal dopamine deficiency leads to hypertension and decreased longevity in mice

Intrarenal dopamine deficiency leads to hypertension and decreased longevity in mice

In addition to its role as an essential neurotransmitter, dopamine serves important physiologic functions in organs such as the kidney. Although the kidney synthesizes dopamine through the actions of aromatic amino acid decarboxylase (AADC) in the proximal tubule, previous studies have not discriminated between the roles of extrarenal and intrarenal dopamine in the overall regulation of renal function. To address this issue, we generated mice with selective deletion of AADC in the kidney proximal tubules (referred to herein as ptAadc –/–

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Renoprotective effect of red grape (Vitis vinifera L.) juice and dark raisins against hypercholesterolaemia-induced tubular renal affection in albino rats

Renoprotective effect of red grape (Vitis vinifera L.) juice and dark raisins against hypercholesterolaemia-induced tubular renal affection in albino rats

Proximal tubules are the first parts of renal tubules where most of the filtered substances are reabsorbed back to blood. Damage of such tubules will result in Figure 1. Sections in renal cortex of rat from the control group (A, B) showing intact proximal tubules (PTs) and distal tubules (DTs) with intact peritubular capillaries while those of the rats fed high cholesterol diet (HCD) (C, D) appear congested and dilated. The PTs of these rats appear dilated with hyaline casts (asterisk) in their lumina and the DTs are lined with cells which have dark cytoplasm and dark nuclei (thick white arrow). Renal tubules of the rats received HCD + red grape juice (RGJ) (E, F) or HCD + dark raisins (DR) (G, H) showing same changes but at lesser extent (haematoxylin and eosin, ×600).
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Development of Severe Hyponatremia due to Salt-Losing Nephropathy after Esophagectomy for Esophageal Cancer

Development of Severe Hyponatremia due to Salt-Losing Nephropathy after Esophagectomy for Esophageal Cancer

We believe that proximal tubular dysfunction existed in the present case. First, urinary concentrations of β2- microglobulin and NAG were high, suggesting proximal tubular injury and dysfunction. Second, hyponatremia and hypouricemia coexisted despite ECV depletion. The reab- sorption of urate occurs mainly in the proximal tubule and is indirectly coupled to sodium reabsorption [5]. Patients with ECV depletion generally have hyperuricemia, because proximal tubules avidly reabsorb sodium together with urate. Therefore, the coexistence of ECV depletion and hypouricemia suggested proximal tubular dysfunction and injury. To show that reabsorption of urate is disturbed, it is essential to calculate fractional excretion of urate (FEUA). Unfortunately, urinary urate was not measured at the first account. We measured urinary urate after her serum urate increase to 3.4 mg/dL, when her FEUA was high at a level of 11.5%. This observation suggest that reabsorption of urate should have been severely disturbed when her serum urate was 1.4 mg/dL. Third, TmP/GFR was relatively low, which is characteristics of SLN and not of SIADH.
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Acquired Fanconi syndrome in patients with Legionella pneumonia

Acquired Fanconi syndrome in patients with Legionella pneumonia

Case presentation: We experienced two male cases of acquired Fanconi syndrome associated with Legionella pneumonia. The laboratory findings at admission showed hypophosphatemia, hypokalemia, hypouricemia and/or hyponatremia. In addition, they had the generalized dysfunction of the renal proximal tubules presenting decreased tubular reabsorption of phosphate (%TRP), increased fractional excretion of potassium (FEK) and uric acid (FEUA), low-molecular-weight proteinuria, panaminoaciduria and glycosuria. Therefore, they were diagnosed as Fanconi syndrome. Treatment for Legionella pneumonia with antibiotics resulted in the improvement of all serum electrolyte abnormalities and normalization of the %TRP, FEK, FEUA, low-molecular-weight proteinuria, panaminoaciduria and glycosuria, suggesting that Legionella pneumophila infection contributed to the pathophysiology of Fanconi syndrome.
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Transforming growth Factor Beta 1 drives a switch in connexin mediated cell to cell communication in tubular cells of the diabetic kidney

Transforming growth Factor Beta 1 drives a switch in connexin mediated cell to cell communication in tubular cells of the diabetic kidney

Background/Aims: Changes in cell-to-cell communication have been linked to several secondary complications of diabetes, but the mechanism by which connexins affect disease progression in the kidney is poorly understood. This study examines a role for glucose- evoked changes in the beta1 isoform of transforming growth factor (TGFβ1), on connexin expression, gap-junction mediated intercellular communication (GJIC) and hemi-channel ATP release from tubular epithelial cells of the proximal renal nephron. Methods: Biopsy material from patients with and without diabetic nephropathy was stained for connexin-26 (CX26) and connexin-43 (CX43). Changes in expression were corroborated by immunoblot analysis in human primary proximal tubule epithelial cells (hPTECs) and model epithelial cells from human renal proximal tubules (HK2) cultured in either low glucose (5mmol/L) ± TGFβ1 (2-10ng/ml) or high glucose (25mmol/L) for 48h or 7days. Secretion of the cytokine was determined by ELISA. Paired whole cell patch clamp recordings were used to measure junctional conductance in control versus TGFβ1 treated (10ng/ml) HK2 cells, with carboxyfluorescein uptake and ATP- biosensing assessing hemi-channel function. A downstream role for ATP in mediating the effects of TGF-β1 on connexin mediated cell communication was assessed by incubating cells with ATPγS (1-100µM) or TGF-β1 +/- apyrase (5 Units/ml). Implications of ATP release were measured through immunoblot analysis of interleukin 6 (IL-6) and fibronectin expression. Results: Biopsy material from patients with diabetic nephropathy exhibited increased tubular expression of CX26 and CX43 (P<0.01, n=10), data corroborated in HK2 and hPTEC cells cultured in TGFβ1 (10ng/ml) for 7days (P<0.001, n=3). High glucose significantly increased
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KCl co transport across the basolateral membrane of rabbit renal proximal straight tubules

KCl co transport across the basolateral membrane of rabbit renal proximal straight tubules

Mammalian renal proximal tubules reabsorb large amounts of chloride. Mechanisms of the transcellular chloride transport are poorly understood. To determine whether KCl co- transport exists in the basolateral membrane of mammalian renal proximal tubule, isolated rabbit proximal straight tubules (S2 segment) were perfused in vitro, and intracellular activities of potassium and chloride (aKi, aCli) were measured by double-barreled ion- selective microelectrodes. aCli did not change when basolateral membrane voltage was altered by application of a direct current through perfusion pipette. aCli changes in response to bath chloride elimination were not affected by current application as well, indicating that the basolateral chloride transport is electroneutral. An increase in potassium concentration of the bath fluid from 5 to 20 mM reversibly increased aCli by 10 mM. This response of aCli to a change in the bath potassium concentration was also observed when luminal chloride was removed, or ambient sodium was totally removed. aKi significantly decreased by 5 mM when chloride was removed from the bath. These data demonstrate the existence of an electroneutral Na+-independent KCl co-transport in the basolateral membrane of the rabbit proximal tubule. Calculated electrochemical driving force was favorable for the movement of KCl from the cell to the peritubular fluid.
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Renin expression in renal proximal tubule

Renin expression in renal proximal tubule

angiotensinogen, angiotensin-converting enzyme, and angiotensin receptors. Previous immunohistochemical studies describing the presence of renin in the proximal tubule could not distinguish synthesized renin from renin trapped from the glomerular filtrate. In the present study, we examined the presence of renin activity and mRNA in rabbit proximal tubule cells in primary culture and renin mRNA in microdissected proximal tubules. Renin activity was present in lysates of proximal tubule cells in primary culture. Cellular renin content in cultured proximal tubule cells was increased by incubation with 10(-5) M isoproterenol and 10(-5) M forskolin by 150 and 110%, respectively. In addition, renin transcripts were detected in poly(A)+ RNA from cultured proximal tubule cells by RNA blots under high stringency conditions. In microdissected tubules from normal rats, renin mRNA was not detectable with reverse transcription and polymerase chain reaction. However, in tubules from rats administered the angiotensinogen-converting-enzyme inhibitor, enalapril, renin was easily detected in the S2 segment of the proximal tubule. We postulate the existence of a local renin-angiotensin system that enables the proximal tubule to generate angiotensin II, thereby providing an autocrine system that could locally modulate NaHCO3 and NaCl absorption.
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Ammonia production by individual segments of the rat nephron

Ammonia production by individual segments of the rat nephron

concentrations in the incubation fluid were measured by microfluorometry to determine ammonia production rates. All segments produced ammonia from glutamine. In normal rats, production with glutamine was highest (greater than 5 pmol/min per mm) in the proximal convoluted (S-1), proximal straight (S-3), and distal convoluted tubules, and lowest (less than or equal to 2) in cortical and medullary collecting ducts and thin descending limbs. Metabolic acidosis increased production by 60% in the S-1 segment of the proximal convoluted tubule and by 150% in the S-2 segment of the proximal straight tubule without significant effect in any other segment. Bicarbonate loading decreased production by S-1 but had no effect on S-2 or S-3. Thus, acid-base changes altered production only in specific segments of the proximal tubule. We infer that the bulk of ammonia production occurs in the proximal tubules and that production by collecting ducts can account for only a few percent of renal ammonia production and excretion in the rat.
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Notch is required for the formation of all nephron segments and primes nephron progenitors for differentiation

Notch is required for the formation of all nephron segments and primes nephron progenitors for differentiation

By employing Wnt4GFPcre, which targets early developing nephrons, we carried out a Notch LOF study. Since it is known that Notch1 and Notch2 act redundantly during nephrogenesis (Surendran et al., 2010), we deleted both Notch1 and Notch2 with Wnt4GFPcre. In order to trace only those nephron progenitors in which Wnt4GFPcre-mediated recombination occurred, we included a lineage tracer (EYFP) in our genetic analysis. It is likely that most of the Wnt4GFPcre-activated Rosa EYFP reporter-positive cells also experienced the deletion of conditional alleles of Notch genes. First, we tested how Wnt4GFPcre-mediated deletion of Notch genes affects nephron segmentation. It was previously thought that Notch signaling promoted the formation of proximal tubules while repressing the formation of distal tubules (Cheng et al., 2007, 2003; Surendran et al., 2010). If this model is correct, blocking Notch signaling in developing nephrons should allow the formation of distal tubules and inhibit the formation of proximal tubules. We examined nephron segmentation in the Notch mutant kidney by immunofluorescence analysis. We used Wt1 ( podocyte), Lotus tetragonolobus lectin (LTL) ( proximal tubule), Slc12a1 (loop of Henle) and Slc12a3 (distal tubule) to mark specific nephron segments (Fig. 2A). In the control kidney, Rosa EYFP reporter-positive cells could differentiate into all segments of the nephron (Fig. 2A, left). By contrast, in the Notch double-mutant kidneys, the Rosa EYFP reporter-labeled cells failed to form any segment of the nephron (Fig. 2A, right).
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