205 results on '"kidney tubule"'
Search Results
52. Intrarenal toll-like receptor 4 and toll-like receptor 2 expression correlates with injury in antineutrophil cytoplasmic antibody-associated vasculitis.
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Holdsworth S.R., Ford S.L., Longano A., Kitching A.R., O'sullivan K.M., Holdsworth S.R., Ford S.L., Longano A., Kitching A.R., and O'sullivan K.M.
- Abstract
In antineutrophil cytoplasmic antibody-associated vasculitis (AAV), Toll-like receptors (TLRs) may be engaged by infection-associated patterns and by endogenous danger signals, linking infection and innate inflammation with this autoimmune disease. This study examined intrarenal TLR2, TLR4, and TLR9 expression and renal injury in AAV, testing the hypothesis that increased TLR expression correlates with renal injury. Patients with AAV exhibited both glomerular and tubulointerstitial expression of TLR2, TLR4, and TLR9, with TLR4 being the most prominent in both compartments. Glomerular TLR4 expression correlated with glomerular segmental necrosis and cellular crescents, with TLR2 expression correlating with glomerular segmental necrosis. The extent and intensity of glomerular and tubulointerstitial TLR4 expression and the intensity of glomerular TLR2 expression inversely correlated with the presenting estimated glomerular filtration rate. Although myeloid cells within the kidney expressed TLR2, TLR4, and TLR9, TLR2 and TLR4 colocalized with endothelial cells and podocytes, whereas TLR9 was expressed predominantly by podocytes. The functional relevance of intrarenal TLR expression was further supported by the colocalization of TLRs with their endogenous ligands high-mobility group box 1 and fibrinogen. Therefore, in AAV, the extent of intrarenal TLR4 and TLR2 expression and their correlation with renal injury indicates that TLR4, and to a lesser degree TLR2, may be potential therapeutic targets in this disease.Copyright © 2018 American Physiological Society. All rights reserved.
- Published
- 2018
53. Reduced tubular degradation of glomerular filtered plasma albumin is a common feature in acute and chronic kidney disease.
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Ly N.D.K., Tesch G.H., Nikolic-Paterson D.J., Poronnik P., Han Y., Ly N.D.K., Tesch G.H., Nikolic-Paterson D.J., Poronnik P., and Han Y.
- Abstract
Tubular epithelial cells take up and degrade plasma albumin filtered by the glomerulus. Tubular damage resulting in reduced albumin uptake or degradation has been suggested as one mechanism contributing to albuminuria in kidney disease. This study investigated whether tubular albumin uptake or degradation is altered in acute and chronic glomerular disease. Mouse models of acute glomerular injury (anti-GBM disease and LPS-induced albuminuria) and chronic disease (streptozotocin-induced diabetes and db/db mice) were examined. Mice were injected intravenously with Alexa-albumin plus DQ-albumin and killed 20 minutes later. Tubular uptake of albumin (Alexa-albumin) and albumin degradation (Dye Quenched (DQ)-albumin) was assessed in tissue sections via confocal microscopy. Tubular uptake of Alexa-albumin in the models of diabetic nephropathy was not different to normal mice. However, the fluorescence signal resulting from degradation of DQ-albumin was significantly reduced in db/db mice, and the ratio of degraded to intact albumin was reduced in both models. The ratio of degraded to intact albumin in tubules was also reduced in the anti-GBM model. In the LPS model, both tubular uptake and degradation of albumin were significantly reduced, with a substantial reduction in the ratio of degraded to intact albumin in tubules. LPS stimulation of cultured tubular epithelial cells inhibited albumin uptake, indicating a direct role for LPS in modifying tubular handling of albumin. In conclusion, reduced degradation of filtered albumin in the proximal tubule is a common feature of glomerular diseases. This may be a general mechanism whereby tubular dysfunction contributes to the development of albuminuria.Copyright © 2017 John Wiley & Sons Australia, Ltd
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- 2018
54. Angiotensin converting enzyme inhibition and chronic cyclosporine-induced renal dysfunction in type 1 diabetes.
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Hannedouche, Thierry P., Natov, Svetlozar, Boitard, Christian, Lacour, Bernard, and Grünfeld, Jean-Pierre
- Abstract
Aim. This study was designed to evaluate whether the angiotensin converting enzyme inhibitor enalapril could prevent cyclosporine-induced renal dysfunction in diabetic patients treated with CsA in monotherapy. Design. Twenty-four recent onset insulin-dependent diabetic patients without prior renal involvement were randomized to receive a 3 month course of either cyclosporine (CsA) alone (7.5 mg/kg. b.i.d. in olive oil) or CsA$enalapril (20 mg p.o. oad.). End points. were mean arterial pressure, plasma creatinine, GFR, renal plasma flow, renal vascular resistance, sodium and lithium clearances measured before and after 3 months of treatment. Results. Baseline values were identical in both groups except for mean arterial pressure which was slightly higher in the subjects subsequently receiving CsA$enalapril. Three month treatment with CsA increased significantly mean arterial pressure and renal vascular resistance by 9 and 24% respectively, while decreasing significantly glomerular filtration rate and renal plasma flow by 17 and 14% respectively. Enalapril was able to prevent the decline in GFR and the increase in blood pressure induced by CsA. This effect was demonstrated despite a similar increase in renal vascular resistance suggesting a dissociation between changes in glomerular filtration rate and renal vascular resistance during angiotensin converting-enzyme inhibition. Conclusion. Chronic angiotensin converting-enzyme inhibition could afford some degree of protection against CsA-induced renal dysfunction. Whether these results can be extrapolated to transplant recipients in whom CsA is usually associated to treatment by glucocorticosteroids, deserves further evaluation. [ABSTRACT FROM PUBLISHER]
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- 1996
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55. Localization and regulation of the renal kallikrein kinin system: Possible relations to renal transport functions.
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Guder, W. and Hallbach, J.
- Abstract
The complete renal kallikrein kinin system has recently been localized in defined nephron segments. Kallikrein was found to be formed and secreted by connecting tubule cells in the late distal convoluted tubule, whereas kininogen and a novel kininase were located in collecting tubules. Kinins were shown to act on collecting tubule as well as medullary interstitial cells and the renal vasculature. The literature on interactions of this system with renal sodium transport is conflicting. Renal and urinary kallikrein was found to be increased under sodium restricted conditions, whereas kinin has a diuretic and natriuretic effect in the collecting tubule, when added from the basolateral surface. On the other hand renal kallikrein activity and connecting tubule cell morphology change in parallel with dietary potassium load indicating a coupling to potassium secretion. The possible role of the renal kallikrein kinin system in regulating collecting tubule function by tubular and vascular effects is outlined in spite of many open questions which remain to be answered. [ABSTRACT FROM AUTHOR]
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- 1988
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56. Face-selective adhesion of calcium oxalate dihydrate crystals to renal epithelial cells.
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Lieske, J., Toback, F., Deganello, S., Lieske, J C, and Toback, F G
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The interaction between the most common urinary crystal, calcium oxalate dihydrate (COD) and the surface of monkey renal epithelial cells of the BSC-1 line was investigated. The [100] face of exogenous COD crystals bound selectively and rapidly to the kidney cell surface. Cellular processes extended preferentially over the [100] face initially, and then progressively covered the crystal so that by 24 hours some crystals were observed beneath the plasma membrane. When nucleated from solution onto the surface of the cell monolayer, COD crystals oriented preferentially so that their [100] faces were in direct contact with the cell surface. In contrast, when siliconized glass was used as a substrate, nucleated COD crystals oriented randomly. Therefore, structures on the apical surface of renal tubular cells that mediate a stereospecific interaction with the molecular array presented by the [100] face of a COD crystal may be important determinants of crystal adhesion that could contribute to crystal retention and formation of kidney stones. [ABSTRACT FROM AUTHOR]
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- 1996
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57. The basement membrane of the atrophic kidney tubule.
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Romen, W. and Mäder-Kruse, I.
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In a light and electron microscopic study of the rat's kidney after obstruction of the renal vein or after subtotal nephrectomy the tubular basement membrane changes occurring during the ensuing atrophy of the tubules have been examined. Characteristically, they consist of diffuse widening, focal thickening with vesicular and granular inclusions, circumscribed dissolution, or reduplication of this structure. These observations have led to the conclusion that the tubular basement membrane is formed by both interstitial and tubular cells, although the interstitial cells contribute the greater share to its formation, maintenance and renewal. The thickening of the basement membrane taking place in tubular atrophy must, however, be attributed entirely to the interstitial cells. [ABSTRACT FROM AUTHOR]
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- 1978
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58. Solvent drag of sucrose during absorption indicates paracellular water flow in the rat kidney proximal tubule.
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Whittembury, Guillermo, Malnic, Gerhard, Mello-Aires, Margarida, and Amorena, Carlos
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Single convoluted proximal tubules of the rat kidney were lumen perfused in situ with isosmotic solutions containing C-sucrose and H-inulin as tracers, to evaluate whether the extracellular marker sucrose is entrained by water during proximal tubular reabsorption. Inulin was used as volume marker. The absorptive rate was varied by using as luminal perfusion fluids either a solution made up of (in mmole/l) 120 NaCl, 5 glucose, 25 NaHCO and altering the perfusion rate, or a solution containing 110 NaCl and 70 raffinose. J, the net sucrose efflux is found to be a function of the net volume flow, J, such that at J=0, J is very small and at high rates of J, J is over 60-fold the value observed at low J values. In addition, the transported to luminal sucrose concentrations decreased with J in a hyperbolic manner. Unstirred layers affect the diffusive component of J, but only to a small extent. Therefore, the large remaining dependency of J with J must be due to drag of sucrose by water, within the paracellular pathway. This leads to the conclusion that water flows through the paracellular pathway during absorption in the rat proximal tubule, in addition to transcellular water flow. Using equations for molecular sieving and the measured value of σ for sucrose of 0.76-0.91, it is calculated that the pathway where entrainment of solute by water occurs must be 1.0-1.1 nm wide. This calculation is only tentative since σ depends on the as yet unknown relative contribution of transcellular and paracellular pathways to transepithelial water osmotic permeability. [ABSTRACT FROM AUTHOR]
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- 1988
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59. Phosphate transport by rat renal brush border membrane vesicles: Influence of dietary phosphate, thyroparathyroidectomy, and 1,25-dihydroxyvitamin D.
- Author
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Stoll, R., Kinne, R., Murer, H., Fleisch, H., and Bonjour, J.
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In the present work we have investigated whether the changes in the renal handling of inorganic phosphate (Pi) induced by 1) dietary Pi, 2) removal of parathyroid glands and 3) 1,25-dihydroxyvitamin D [1,25(OH)D], are associated with alterations in the Na-dependent Pi uptake by brush border membrane vesicles (BBMV) isolated from renal cortex. Shamoperated (SHAM) or thyroparathyroidectomized (TPTX) rats treated or not with 26 pmol/day of 1,25 (OH)Di.p. were fed low (0.2%) or high (1.2%)P diet for 7 days. The results showed that in SHAM, TPTX and TPTX+1,25 (OH)D the Pi uptake by BBMV was greater after low than high Pi diet. It was greater in TPTX than in SHAM counterparts fed either diets. In TPTX fed low or high Pi diet 1,25 (OH)D decreased the Pi uptake to the level observed in SHAM. A striking parallelism was found between variations in Pi uptake by BBMV and in the tubular Pi reabsorption of the whole kidney. The Na-dependent glucose, the mannitol uptake by BBMV, and the alkaline phosphatase activity in cortical homogenates and BBMV were not affected by the various treatments. Thus, dietary Pi, chronic TPTX and 1,25 (OH)D appear to specifically affect the Na-dependent Pi transport system bound to the brush border membranes of renal cortical tubules. The alterations observed at this membrane level could account, at least in part, for the changes induced by these three factors on the overall tubular reabsorption of Pi. [ABSTRACT FROM AUTHOR]
- Published
- 1979
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60. Effects of furosemide, acetazolamide, and mannitol on medullary collecting-duct function in the rat kidney.
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Sonnenberg, Harald
- Abstract
The microcatheterization technique was used to study transport of fluid, sodium, and potassium in the medullary collecting duct in rats (232-357 g) before and during administration of diuretic drugs. Series I received furosemide (1.5 mg initial dose + 1.5 mg/h), Series II acetazolamide (0.75 mg +0.75 mg/h), and Series III and IV mannitol at 0.3 g+0.3 g/h, and 0.3 g+1.0 g/h, respectively. All diuretics caused diuresis, natriuresis, and kaliuresis. The renal response to furosemide and acetazolamide was associated with increased hematocrit and decreased filtration rate, indicating depletion of blood volume. No such effect was seen in Series III and IV. In the collecting duct furosemide completely abolished the normal reabsorption of sodium and fluid and initiated net secretion of potassium. Partial inhibition of salt and water transport in the collecting duct was observed with acetazolamide and the low dose of mannitol (III). Both treatments resulted in potassium secretion. In Series IV the high rate of mannitol infusion was associated with complete inhibition of salt and water reabsorption from the medullary collecting system similar to that of Series I. The greater excretory response in this group compared to the furosemide series was due to increased delivery of tubular load to the collecting duct. It is concluded that a major site of action of furosemide is in the medullary duct, resulting in quantitative inhibition of salt and water reabsorption from this nephron segment. The partial transport inhibition during acetazolamide or modest mannitol diuresis can be explained by the presence of poorly absorbable solute in duct fluid. The mechanism of inhibition of reabsorption after the high rate of mannitol infusion remains undetermined. [ABSTRACT FROM AUTHOR]
- Published
- 1978
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61. Phosphate, calcium and magnesium fluxes into the lumen of the rat proximal convoluted tubule.
- Author
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Shirley, D., Poujeol, P., and Grimellec, C.
- Abstract
In order to study fluxes of phosphate (P), Ca and Mg into the rat proximal tubule, a modification of the split-droplet microinjection technique was used. Injected fluids were isotonic solutions containing no P, Ca or Mg. The initial NaCl concentration of the injectates was either (a) 115 mM/l (which resulted in net fluid entry into the lumen), (b) 125 mM/l (no net fluid movement) or (c) 150 mM/l (net reabsorption of fluid). Injected droplets were subsequently collected from the nephron and their ionic concentrations determined using electron probe analysis. All 3 ions entered the tubular lumen. For the 115 mM and 125 mM NaCl injectates, P concentration increased for the first 15 s, then reached steady values of 2.07 mM/l and 2.30 mM/l respectively. Using 150 mM NaCl as injectate, P concentration increased for only 10 s, and then reached an average value of 2.04 mM/l. Ca and Mg concentrations in reaspirated droplets showed no correlation with time, indicating that entry into the lumen was almost immediate. The mean Ca concentration using 115 mM NaCl injectate was 1.63 mM/l, higher than with equilibrated or reabsorbed injectates (1.01 and 1.15 mM/l respectively). Mg concentration following injection of 115 mM NaCl solution (0.45 mM/l) was lower than with the other 2 injectates (0.92 and 0.85 mM/l). It is suggested that P and Mg enter the proximal tubular lumen from the tubular cells, while Ca entry may be transtubular and take place via intercellular pathways. [ABSTRACT FROM AUTHOR]
- Published
- 1976
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62. Phosphate transport by isolated renal brush border vesicles.
- Author
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Hoffmann, N., Thees, M., and Kinne, R.
- Abstract
A sodium dependent specific transport system for phosphate is present in the brush border microvilli but absent from the basal-lateral plasma membranes. The apparent affinity of this transport system for phosphate is 0.08 mM at 100 mM sodium and pH 7.4. It is inhibited competitively by arsenate with an apparent inhibitor constant of 1.1 mM (100 mM sodium, pH 7.4). Sodium dependent phosphate uptake is two times higher at pH 8 compared to the uptake observed at pH 6. The apparent affinity of the transport system for sodium is also pH-dependent, half-maximal stimulation of uptake is found at pH 6 with 129 mM sodium, at pH 7.4 with 60 mM sodium and at pH 8 with 50 mM sodium. Under all conditions a nonhyperbolic dependence of phosphate uptake on the sodium concentration is observed. The uptake of phosphate by brush border microvilli vesicles shows a typical overshoot phenomenon in the presence of sodium gradient across the membrane $$(C_{Na_o } > {\text{ }}C_{Na_i } )$$ . The amount of phosphate taken up after 2 min is about twice the equilibrium value reached after 2 h of incubation. At pH 7.4 the initial rate of uptake is increased only slightly (12%) by inside negative membrane diffusion potentials and inhibited to the same extent by inside positive membrane diffusion potentials. These results indicate that the entry of phosphate across the brush border membrane into the epithelial cell of the proximal tubule is coupled to the entry of sodium. The transfer of phosphate is dependent on its concentration gradient and on the concentration difference of sodium. The data are best explained by the following hypothesis: Both the primary phosphate as well as the secondary phosphate are transported in cotransport with sodium. The divalent form however seems to be transported preferentially. Its transport occurs electroneutral with 2 sodium ions; the monovalent phosphate also enters the cell together with 2 sodium ions but as a positively charged complex. The exit of phosphate across the contraluminal cell border is sodium independent and is favoured by the high intracellular phosphate concentration and the inside negative membrane potential. [ABSTRACT FROM AUTHOR]
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- 1976
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63. Transport of p-aminohippuric acid by plasma membrane vesicles isolated from rat kidney cortex.
- Author
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Berner, W. and Kinne, R.
- Abstract
Basal-lateral plasma membrane vesicles and brush border membrane vesicles were isolated from rat kidney cortex and the uptake of p-amino-hippuric acid (PAH) into these vesicles was studied by Millipore filtration techniques. Both membrane preparations take up PAH into an osmotically reactive intravesicular space. The transport across the brush border membrane seems to involve only simple diffusion whereas in the basal-lateral plasma membrane in addition a specific transport system exists which is inhibited competitively by probenecid. The apparent affinity of this transport system for PAH is 5.4×10 M and for probenecid 5.4×10 M. PAH uptake into basal-lateral plasma membrane vésicles is influenced by alteration of the membrane potential. Maneuvers which render the intravesicular space more positive-as for example replacement of chloride by sulfate in the presence of a sodium gradient directed into the vesicles and addition of valinomycin in the presence of a potassium gradient directed into the vesicles-stimulate the uptake of PAH. Replacement of a sodium chloride gradient by a sodium thiocyanate gradient reduces the uptake probably by reducing the inside positive membrane potential. In the absence of salt gradients anion replacement and replacement of sodium by potassium does not affect PAH transport by basal-lateral plasma membranes. These results suggest that in isolated basal-lateral membranes transfer of PAH across the membrane is accompanied by a transfer of negative charge. They furthermore provide no evidence for the existence of a sodium-PAH cotransport system in this membrane preparation. [ABSTRACT FROM AUTHOR]
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- 1976
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64. Microperfusion study of the kinetics of reabsorption of cycloleucine in early and late segments of the proximal convolution of the rat nephron.
- Author
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Lingard, J., Györy, A., and Young, J.
- Abstract
The proximal tubular reabsorptive capacity for the non-metabolizable amino acid, cycloleucine, was studied in the rat nephron by stationary microperfusion. Tubular reabsorptive rates were greatest near the glomerulus and declined progressively along the convolution. A kinetic analysis of cycloleucine reabsorption in terms of luminal concentration revealed that this reduced transport rate was associated with an increase in the half-saturation constant of the kinetic curve, rather than a decrease in the maximum transport capacity. Since our previous findings with the metabolizable amino acid, l-histidine, were identical we can conclude that this decline in reabsorption of neutral amino acids as a function of distance along the convolution is an intrinsic property of the transport system and is not related to tubule cell amino acid metabolism. The transport curves for cycloleucine absorption did not give a simple Michaelis-Menten relation but rather followed a course suggesting that more than one transport system might be involved. [ABSTRACT FROM AUTHOR]
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- 1975
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65. Micropuncture study along the proximal convoluted tubule electrolyte reabsorption in first convolutions.
- Author
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Grimellec, Christian, Giocondi, M., and Philippe, P.
- Abstract
126 micropunctures were performed on 40 Bowman's capsules as well as along the corresponding proximal convoluted tubules (PCT) on six non-diuretic rats. Capsular and tubular fluid samples (GF and TF) collected were analysed for Na, Cl, K, P, Ca, Mg andH-Inulin concentrations by electron probe analysis and liquid scintillation. Electrolyte handling along the usually inaccessible part of the PCT, i.e. EPCT, was determined by selecting from the samples collected in the first two or three proximal loops, those having a (TF/GF) In value ≤1.15. Except for Na the concentration of electrolytes was significantly modified when the fluid flowed along the PCT: 1. In the EPCT, (TF/GF) Cl and K rose and (TF/GF) P dropped in correlation with (TF/GF) In. For (TF/GF) In=1.15, (TF/GF) chloride, potassium and phosphate were respectively equal to 1.12, 1.10 and 0.72. These values were comparable to those obtained in the remaining length of PCT, indicating that the chemical gradient established in the first loops was maintained in the subsequent ones. Therefore proximal handling of these three ions differed depending on the PCT portion considered. The reasons for this difference are discussed further on. 2. Calcium concentration increased and reached a plateau corresponding to (TF/GF)Ca=1.22 for (TF/GF) In values ranging from 1.31 to 1.45. 3. Magnesium was not reabsorbed for (TF/GF) In values below 1.90. Above this level slight Mg reabsorption occurred. 4. Significant correlations between (TF/GF) K, Ca and P and (TF/GF) Cl ratios were observed along the PCT, suggesting that proximal reabsorption of K, Ca and P was dependent on tubular fluid acidification. [ABSTRACT FROM AUTHOR]
- Published
- 1975
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66. Phenomenologic description of Na, Cl and HCO absorption from proximal tubules of the rat kidney.
- Author
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Frömter, E., Rumrich, G., and Ullrich, K.
- Abstract
Proximal tubules of the rat kidney were perfused in vivo with NaCl-NaHCO Ringer's solution and the net rates of fluid absorption from Gertz shrinking drops were measured as well as the stationary electro-chemical potential differences for Na and Cl that develop across the tubular wall during constant fluid absorption. By altering the rate of fluid absorption through addition of raffinose to the peritubular perfusate or to the lumen fluid, the relations between the net ion fluxes and the electrochemical potential differences were obtained for Na, Cl and HCO. From these relations which were reasonably linear for Na and Cl over small deviations from equilibrium, single ion reflection coefficients and active transport rates were calculated. Since the calculations required a knowledge of the permeability coefficients of the tubular wall for Na and Cl, in a separate series of experiments these coefficients were determined from tracer flux experiments. The calculations yield σ=0.7, and σ=0.5 $$\sigma _{HCO_2 } $$ can be estimated to be substantially greater than σ. Comparing the active transport rates to the net fluid absorption under conditions similar to free flow in the normal kidney, the following conclusions can be drawn: approximately one third of the sodium is resorbed by active transport, one third by electrical transference and one third by solvent drag. Chloride transport is entirely passive. One half of the chloride is resorbed by diffusion and one half by solvent drag. Bicarbonate transport appears to be entirely active, and the active transport rate is greater than the net transport pointing to passive bicarbonate back flux. [ABSTRACT FROM AUTHOR]
- Published
- 1973
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67. Calcium-dependent control of volume regulation in renal proximal tubule cells: II. Roles of dihydropyridine-sensitive and-insensitive Ca entry pathways.
- Author
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McCarty, Nael and O'Neil, Roger
- Abstract
The Ca entry pathways in the basolateral plasma membrane of the isolated, nonperfused proximal straight tubule (PST) of rabbit kidney were investigated using fura-2 fluorescence microscopy. Under isotonic conditions, reduction of bath [Ca] from 1 mM to 1 μM caused intracellular free calcium concentration ([Ca]) to fall close to zero. Treatment with 10 μM verapamil, a calcium channel blocker, had a similar effect. Treatment with verapamil or low Ca also induced fluctuations in cell volume. However, isotonic treatment with 10 μM nifedipine, a dihydropyridine (DHP)-type calcium channel blocker, did not affect [Ca] or cell volume, indicating that the endogenous Ca entry pathway is verapamil-sensitive but DHP-insensitive. When cells were exposed to hypotonic solutions in the presence of 1 mM Ca, they swelled and underwent normal RVD while [Ca] increased transiently to a peak before decreasing to a late phase plateau level above the baseline level ( see McCarty, N.A., O'Neil, R.G. 1991. J. Membrane Biol. 123:149-160). When cells were swollen in the presence of verapamil or low bath [Ca], RVD was abolished and [Ca] fell well below the baseline during the late phase response. In contrast, when cells were swollen in the presence of nifedipine, RVD and the late phase rise in [Ca] were abolished, but [Ca] did not fall below the baseline level in the late phase, indicating that nifedipine inhibited the swelling-induced Ca entry but that Ca entry by another pathway was undisturbed. It was concluded that PST cells are characterized by two Ca permeability pathways in the basolateral membrane. Under both isotonic and hypotonic conditions, Ca entry occurs at a slow rate via a verapamil-sensitive, DHP-insensitive 'baseline' Ca entry pathway. Cell swelling activates a separate DHP-sensitive, verapamil-sensitive Ca entry pathway, which is responsible for the supply of Ca ions to the Ca-dependent mechanism by which cell volume regulation is achieved. [ABSTRACT FROM AUTHOR]
- Published
- 1991
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68. Effect of Intensive Blood Pressure Lowering on Kidney Tubule Injury: Findings From the ACCORD Trial Study Participants
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Joachim H. Ix, Michael G. Shlipak, Chirag R. Parikh, Kinsuk Chauhan, Girish N. Nadkarni, Veena Rao, and Steven G. Coca
- Subjects
Male ,Kidney Disease ,estimated glomerular filtration rate ,030232 urology & nephrology ,eGFR decline ,hemodynamics ,Cardiovascular ,0302 clinical medicine ,Chronic kidney disease ,030212 general & internal medicine ,Longitudinal Studies ,Renal Insufficiency ,Chronic ,blood pressure ,tubular injury ,Middle Aged ,Urology & Nephrology ,urine ,Kidney Tubules ,Nephrology ,6.1 Pharmaceuticals ,Hypertension ,Public Health and Health Services ,Biomarker (medicine) ,Female ,Glomerular Filtration Rate ,intensive BP control ,medicine.medical_specialty ,Randomization ,hypertension ,Urinary system ,CKD progression ,Clinical Trials and Supportive Activities ,Clinical Sciences ,Renal and urogenital ,Subgroup analysis ,Article ,03 medical and health sciences ,Clinical Research ,Internal medicine ,medicine ,Humans ,urinary biomarkers ,Renal Insufficiency, Chronic ,Aged ,kidney tubule ,Random assignment ,business.industry ,Prevention ,Evaluation of treatments and therapeutic interventions ,medicine.disease ,Clinical trial ,renal perfusion ,Blood pressure ,Good Health and Well Being ,business ,Biomarkers ,Kidney disease - Abstract
Rationale & objectiveRandom assignment to intensive blood pressure (BP) lowering (systolic BP
- Published
- 2018
69. Impaired mitophagy links mitochondrial disease to epithelial stress in methylmalonyl-CoA mutase deficiency
- Author
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Luciani, Alessandro, Schumann, Anke, Berquez, Marine, Chen, Zhiyong, Nieri, Daniela, Failli, Mario, Debaix, Huguette, Festa, Beatrice Paola, Tokonami, Natsuko, Raimondi, Andrea, Cremonesi, Alessio, Carrella, Diego, Forny, Patrick, Kölker, Stefan, Diomedi Camassei, Francesca, Diaz, Francisca, Moraes, Carlos T, Di Bernardo, Diego, Baumgartner, Matthias R, Devuyst, Olivier, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, University of Zurich, and Luciani, Alessandro
- Subjects
Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Mitochondrial Diseases ,Science ,Ubiquitin-Protein Ligases ,Cell Damage ,General Physics and Astronomy ,610 Medicine & health ,1600 General Chemistry ,Genetics and Molecular Biology ,Article ,Gene Knockout Techniques ,Mice ,1300 General Biochemistry, Genetics and Molecular Biology ,Stress, Physiological ,Chronic kidney disease ,Animals ,Humans ,Organelle Quality Control ,lcsh:Science ,Amino Acid Metabolism, Inborn Errors ,Zebrafish ,Mice, Knockout ,Alkyl and Aryl Transferases ,Kidney Tubule ,Autophagosomes ,Mitophagy ,nutritional and metabolic diseases ,Membrane Proteins ,Methylmalonyl-CoA Mutase ,Epithelial Cells ,General Chemistry ,Inherited Metabolic Disorders ,Microreview ,3100 General Physics and Astronomy ,Mitochondria ,Disease Models, Animal ,Oxidative Stress ,Mechanisms of disease ,Metabolism ,10036 Medical Clinic ,General Biochemistry ,lcsh:Q ,Female ,Protein Kinases ,Metabolism, Inborn Errors - Abstract
Deregulation of mitochondrial network in terminally differentiated cells contributes to a broad spectrum of disorders. Methylmalonic acidemia (MMA) is one of the most common inherited metabolic disorders, due to deficiency of the mitochondrial methylmalonyl-coenzyme A mutase (MMUT). How MMUT deficiency triggers cell damage remains unknown, preventing the development of disease–modifying therapies. Here we combine genetic and pharmacological approaches to demonstrate that MMUT deficiency induces metabolic and mitochondrial alterations that are exacerbated by anomalies in PINK1/Parkin–mediated mitophagy, causing the accumulation of dysfunctional mitochondria that trigger epithelial stress and ultimately cell damage. Using drug–disease network perturbation modelling, we predict targetable pathways, whose modulation repairs mitochondrial dysfunctions in patient–derived cells and alleviate phenotype changes in mmut–deficient zebrafish. These results suggest a link between primary MMUT deficiency, diseased mitochondria, mitophagy dysfunction and epithelial stress, and provide potential therapeutic perspectives for MMA., Methylmalonic acidemia is an inherited metabolic disease caused by loss or mutation of the enzyme MMUT. Here the authors use cell and animal models to show that MMUT mutations lead to defective mitophagy and stress in kidney cells, contributing to the pathogenesis in methylmalonic acidemia patients.
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- 2018
70. Single-Nucleus RNA Sequencing Identifies New Classes of Proximal Tubular Epithelial Cells in Kidney Fibrosis.
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Lu YA, Liao CT, Raybould R, Talabani B, Grigorieva I, Szomolay B, Bowen T, Andrews R, Taylor PR, and Fraser D
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- Animals, Aristolochic Acids, Cell Communication, Cell Movement, Cell Nucleus, Chromosome Mapping, Epithelial Cells physiology, Fibroblasts metabolism, Fibrosis, Macrophages metabolism, Male, Mice, RNA genetics, Regeneration, Sequence Analysis, RNA, Epithelial Cells metabolism, Epithelial Cells pathology, Kidney Tubules, Proximal pathology, Phenotype, RNA metabolism, Transcriptome
- Abstract
Background: Proximal tubular cells (PTCs) are the most abundant cell type in the kidney. PTCs are central to normal kidney function and to regeneration versus organ fibrosis following injury. This study used single-nucleus RNA sequencing (snRNAseq) to describe the phenotype of PTCs in renal fibrosis., Methods: Kidneys were harvested from naïve mice and from mice with renal fibrosis induced by chronic aristolochic acid administration. Nuclei were isolated using Nuclei EZ Lysis buffer. Libraries were prepared on the 10× platform, and snRNAseq was completed using the Illumina NextSeq 550 System. Genome mapping was carried out with high-performance computing., Results: A total of 23,885 nuclei were analyzed. PTCs were found in five abundant clusters, mapping to S1, S1-S2, S2, S2-cortical S3, and medullary S3 segments. Additional cell clusters ("new PTC clusters") were at low abundance in normal kidney and in increased number in kidneys undergoing regeneration/fibrosis following injury. These clusters exhibited clear molecular phenotypes, permitting labeling as proliferating, New-PT1, New-PT2, and (present only following injury) New-PT3. Each cluster exhibited a unique gene expression signature, including multiple genes previously associated with renal injury response and fibrosis progression. Comprehensive pathway analyses revealed metabolic reprogramming, enrichment of cellular communication and cell motility, and various immune activations in new PTC clusters. In ligand-receptor analysis, new PTC clusters promoted fibrotic signaling to fibroblasts and inflammatory activation to macrophages., Conclusions: These data identify unrecognized PTC phenotype heterogeneity and reveal novel PTCs associated with kidney fibrosis., (Copyright © 2021 by the American Society of Nephrology.)
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- 2021
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71. Biomarkers of Kidney Tubule Health, CKD Progression, and Acute Kidney Injury in SPRINT (Systolic Blood Pressure Intervention Trial) Participants.
- Author
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Bullen AL, Katz R, Jotwani V, Garimella PS, Lee AK, Estrella MM, Shlipak MG, and Ix JH
- Subjects
- Acute Kidney Injury pathology, Acute Kidney Injury physiopathology, Aged, Biomarkers urine, Disease Progression, Female, Fibroblast Growth Factor-23, Humans, Kidney Function Tests, Kidney Tubules pathology, Male, Middle Aged, Acute Kidney Injury metabolism, Blood Pressure physiology, Glomerular Filtration Rate physiology, Kidney Tubules metabolism
- Abstract
Rationale & Objective: The Systolic Blood Pressure Intervention Trial (SPRINT) compared the effect of intensive versus standard systolic blood pressure targets on cardiovascular morbidity and mortality. In this ancillary study, we evaluated the use of exploratory factor analysis (EFA) to combine biomarkers of kidney tubule health in urine and plasma and then study their role in longitudinal estimated glomerular filtration rate (eGFR) change and risk of acute kidney injury (AKI)., Study Design: Observational cohort nested in a clinical trial., Setting & Participants: 2,351 SPRINT participants with eGFR < 60 mL/min/1.73 m
2 at baseline., Exposure: Levels of neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), chitinase-3-like protein (YKL-40), kidney injury molecule 1 (KIM-1), monocyte chemoattractant protein 1 (MCP-1), α1 -microglobulin (A1M) and β2 -microglobulin (B2M), uromodulin (UMOD), fibroblast growth factor 23 (FGF-23), and intact parathyroid hormone (PTH)., Outcome: Longitudinal changes in eGFR and risk of AKI., Analytical Approach: We performed EFA to capture different tubule pathophysiologic processes. We used linear mixed effects models to evaluate the association of each factor with longitudinal changes in eGFR. We evaluated the association of the tubular factors scores with AKI using Cox proportional hazards regression., Results: From 10 biomarkers, EFA generated 4 factors reflecting tubule injury/repair (NGAL, IL-18, and YKL-40), tubule injury/fibrosis (KIM-1 and MCP-1), tubule reabsorption (A1M and B2M), and tubule reserve/mineral metabolism (UMOD, FGF-23, and PTH). Each 1-SD higher tubule reserve/mineral metabolism factor score was associated with a 0.58% (95% CI, 0.39%-0.67%) faster eGFR decline independent of baseline eGFR and albuminuria. Both the tubule injury/repair and tubule injury/fibrosis factors were independently associated with future risk of AKI (per 1 SD higher, HRs of 1.18 [95% CI, 1.10-1.37] and 1.23 [95% CI, 1.02-1.48], respectively)., Limitations: The factors require validation in other settings., Conclusions: EFA allows parsimonious subgrouping of biomarkers into factors that are differentially associated with progressive eGFR decline and AKI. These subgroups may provide insights into the pathological processes driving adverse kidney outcomes., (Published by Elsevier Inc.)- Published
- 2021
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72. Enhanced glomerular Toll-like receptor 4 expression and signaling in patients with type 2 diabetic nephropathy and microalbuminuria
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Elena D'Amato, Mariano Mij, Fabio Gianiorio, Giacomo Garibotto, Gennaro Salvidio, Laura Cappuccino, Alchiede Simonato, Barbara Villaggio, Francesca Viazzi, Daniela Verzola, Verzola, Daniela, Cappuccino, Laura, D'Amato, Elena, Villaggio, Barbara, Gianiorio, Fabio, Mij, Mariano, Simonato, Alchiede, Viazzi, Francesca, Salvidio, Gennaro, and Garibotto, Giacomo
- Subjects
Male ,Kidney Glomerulus ,Diabetic nephropathy ,urologic and male genital diseases ,nefropatiadiabetica ,Diabetic Nephropathies ,Minimal change disease ,Chemokine CCL5 ,Kidney ,Middle Aged ,Up-Regulation ,Kidney Tubules ,medicine.anatomical_structure ,Nephrology ,Disease Progression ,Female ,Human ,Signal Transduction ,medicine.medical_specialty ,Receptors, CCR5 ,Receptors, CCR2 ,Nephrosis ,Antigens, Differentiation, Myelomonocytic ,Follow-Up Studie ,Nephropathy ,Toll-like receptor ,Antigens, CD ,Diabetes mellitus ,Internal medicine ,medicine ,Albuminuria ,Humans ,RNA, Messenger ,Inflammation ,Interleukin-6 ,Tumor Necrosis Factor-alpha ,business.industry ,Nephrosis, Lipoid ,Kidney Tubule ,Transcription Factor RelA ,Biomarker ,medicine.disease ,Immunity, Innate ,Toll-Like Receptor 4 ,Endocrinology ,Diabetes Mellitus, Type 2 ,Diabetic Nephropathie ,TLR4 ,Microalbuminuria ,Kidney Glomerulu ,business ,Biomarkers ,Follow-Up Studies - Abstract
Toll-like receptor 4 (TLR4), a component of the innate immune system, is recognized to promote tubulointerstitial inflammation in overt diabetic nephropathy (DN). However, there is no information on immune activation in resident renal cells at an early stage of human DN. In order to investigate this, we studied TLR4 gene and protein expression and TLR4 downward signaling in kidney biopsies of 12 patients with type 2 diabetes and microalbuminuria, and compared them with 11 patients with overt DN, 10 with minimal change disease (MCD), and control kidneys from 13 patients undergoing surgery for a small renal mass. Both in microalbuminuria and in overt DN, TLR4 mRNA and protein were overexpressed 4- to 10-fold in glomeruli and tubules compared with the control kidney and in MCD. In addition, NF-κB signaling was about fourfold higher in the glomeruli. TNF-α, IL6, CCR2, CCL5, and CCR5 mRNAs were markedly (about three- to fivefold) upregulated in microdissected glomeruli. While IL6, CCL2 and CCR5-mRNA, and CD68 were overexpressed in the tubulointerstitial compartment in clinical DN, they were not expressed in microalbuminuria. In a 6-year follow-up of microalbuminuric patients, glomerular TLR4 gene expression was associated with the subsequent loss of kidney function. Thus, innate immunity is activated in the glomeruli of patients with diabetic microalbuminuria. Enhanced TLR4 signaling may contribute to the progression occurring after the incipient, microalbuminuric form of nephropathy evolves to overt disease.
- Published
- 2014
73. Correction: Inherited Tubulopathies of the Kidney: Insights from Genetics.
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- 2021
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74. Protective effects of diltiazem and tadalafil on shock wave-induced kidney injury in rats
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O Kaygisiz, H Vuruskan, G Ozmerdiven, B A Vuruskan, Uludağ Üniversitesi/Tıp Fakültesi/Üroloji Anabilim Dalı., Uludağ Üniversitesi/Tıp Fakültesi/Patoloji Anabilim Dalı., Özmerdiven, Gökhun, Vuruşkan, Berna Aytaç, Kaygısız, Onur, Vuruşkan, Hakan, AAH-9746-2021, AAM-9726-2020, and L-9439-2019
- Subjects
Male ,medicine.medical_treatment ,Kidney Glomerulus ,Ischemia/reperfusion injury ,030204 cardiovascular system & hematology ,Nephrectomy ,Tadalafil ,Rats, Sprague-Dawley ,Tubular dysfunction ,Diltiazem ,0302 clinical medicine ,Lithotripsy ,Mechanisms ,Pathology ,Materials Chemistry ,Renal tubules ,Injuries ,Heat shock protein ,Ultrasonic Lithotripsy ,Shock Waves ,Urolithiasis ,05 social sciences ,Forestry ,Acute Kidney Injury ,Medicine, general & internal ,Sprague dawley rat ,Combination drug therapy ,Kidney Tubules ,Shock (circulatory) ,Reperfusion Injury ,Drug Therapy, Combination ,Renal ischemia-reperfusion ,medicine.symptom ,medicine.drug ,Economics and Econometrics ,medicine.medical_specialty ,Nifedipine ,Allopurinol ,Ischemia ,Urology ,Ischemia-reperfusion injury ,Protective Agents ,03 medical and health sciences ,0502 economics and business ,Media Technology ,medicine ,Animals ,Cell damage ,Pig ,Kidney tubule ,Drug effects ,Adverse effects ,Animal ,urogenital system ,business.industry ,Shock wave lithotripsy ,medicine.disease ,Rats ,Verapamil ,Glomerulus ,Rat ,Calcium ,050211 marketing ,General & internal medicine ,Protective agent ,business ,Reperfusion injury - Abstract
Background We aimed to compare the protective effects of tadalafil and diltiazem on renal histology after ischemia and reperfusion injury in a rat model of shock wave lithotripsy. Methods A total of 40 adult, male Sprague-Dawley rats were randomized into four groups as follows; control group (group C), group S (SWL + nephrectomy), group T (SWL + tadalafil given before nephrectomy) and group D (SWL + diltiazem given before nephrectomy). Both kidneys were evaluated regarding tubular damage, peritubular fibrosis and heat shock protein-70 (HSP-70) immune-expression of glomeruli, cortical and medullar collector tubules on light microscopy. Results HSP-70 levels of cortical and medullar collector tubules, tubular damage and peritubular fibrosis scores were decreased in group T compared with group S. Similarly, HSP-70 immunostaining levels on cortical and medullar collector tubules, tubular damage and peritubular fibrosis scores were decreased in group D compared with group S. No significant difference was detected between group D and group T for all parameters. Conclusion As a result, shock waves induced renal cell damage due to increment of HSP-70 levels, morphological irregularity in tubules and increased peritubular fibrosis. Tadalafil and diltiazem had beneficial effects in decreasing renal tissue damage which was caused by SWL (Tab. 2, Fig. 6, Ref. 29).
- Published
- 2017
75. Mitogen-Activated Protein Kinase 14 Promotes AKI
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Maria Dolores Sanchez-Niño, Harald Mischak, Tonia Vlahou, Laura González-Lafuente, William Mullen, Alberto Ortiz, Lara Valiño-Rivas, Amaya Albalat, Manuel Fresno, Sergio Mezzano, Holger Husi, and Ana Belen Sanz
- Subjects
0301 basic medicine ,renal failure ,Programmed cell death ,renal injury ,030232 urology & nephrology ,Biology ,Nephropathy ,Mitogen-Activated Protein Kinase 14 ,03 medical and health sciences ,MAP3K14 ,Mice ,0302 clinical medicine ,medicine ,Animals ,Protein kinase A ,Kidney ,kidney tubule ,NIK ,Kinase ,RELB ,chemokine ,Acute kidney injury ,apoptosis ,non-canonical NFκB ,General Medicine ,medicine.disease ,3. Good health ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Basic Research ,acute kidney injury ,Nephrology ,inflammation ,Cancer research ,Female ,tissue proteomics - Abstract
An improved understanding of pathogenic pathways in AKI may identify novel therapeutic approaches. Previously, we conducted unbiased liquid chromatography-tandem mass spectrometry-based protein expression profiling of the renal proteome in mice with acute folate nephropathy. Here, analysis of the dataset identified enrichment of pathways involving NFκB in the kidney cortex, and a targeted data mining approach identified components of the noncanonical NFκB pathway, including the upstream kinase mitogen-activated protein kinase kinase kinase 14 (MAP3K14), the NFκB DNA binding heterodimer RelB/NFκB2, and proteins involved in NFκB2 p100 ubiquitination and proteasomal processing to p52, as upregulated. Immunohistochemistry localized MAP3K14 expression to tubular cells in acute folate nephropathy and human AKI. In vivo, kidney expression levels of NFκB2 p100 and p52 increased rapidly after folic acid injection, as did DNA binding of RelB and NFκB2, detected in nuclei isolated from the kidneys. Compared with wild-type mice, MAP3K14 activity-deficient aly/aly (MAP3K14(aly/aly)) mice had less kidney dysfunction, inflammation, and apoptosis in acute folate nephropathy and less kidney dysfunction and a lower mortality rate in cisplatin-induced AKI. The exchange of bone marrow between wild-type and MAP3K14(aly/aly) mice did not affect the survival rate of either group after folic acid injection. In cultured tubular cells, MAP3K14 small interfering RNA targeting decreased inflammation and cell death. Additionally, cell culture and in vivo studies identified the chemokines MCP-1, RANTES, and CXCL10 as MAP3K14 targets in tubular cells. In conclusion, MAP3K14 promotes kidney injury through promotion of inflammation and cell death and is a promising novel therapeutic target.
- Published
- 2017
76. Common variants in CLDN14 are associated with differential excretion of magnesium over calcium in urine
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Pascal Houillier, Peter Vollenweider, Olivier Devuyst, Sheila Ulivi, Murielle Bochud, Ozren Polasek, Hendrica Belge, Michela Traglia, Caroline Hayward, Paolo Gasparini, Tanguy Corre, John M. Starr, Stefania Lenarduzzi, Olivier Bonny, Sarah E. Harris, Daniela Toniolo, Eric Olinger, Natsuko Tokonami, Sonia Youhanna, Ian J. Deary, University of Zurich, Devuyst, Olivier, Corre, Tanguy, Olinger, Eric, Harris, Sarah E., Traglia, Michela, Ulivi, Sheila, Lenarduzzi, Stefania, Belge, Hendrica, Youhanna, Sonia, Tokonami, Natsuko, Bonny, Olivier, Houillier, Pascal, Polasek, Ozren, Deary, Ian J., Starr, John M., Toniolo, Daniela, Gasparini, Paolo, Vollenweider, Peter, Hayward, Caroline, and Bochud, Murielle
- Subjects
0301 basic medicine ,Claudin-14 ,GWAS ,Mg/Ca ratio ,Tubular functions ,Animals ,Calcium ,Claudins ,Humans ,Kidney Tubules ,Magnesium ,Polymorphism, Single Nucleotide ,Urine ,Physiology ,Clinical Biochemistry ,Physiology (medical) ,medicine.medical_specialty ,Candidate gene ,Urinary system ,Population ,Single-nucleotide polymorphism ,Genome-wide association study ,610 Medicine & health ,Biology ,1308 Clinical Biochemistry ,10052 Institute of Physiology ,Excretion ,03 medical and health sciences ,2737 Physiology (medical) ,Internal medicine ,Tubular function ,medicine ,Polymorphism ,education ,education.field_of_study ,Animal ,Kidney Tubule ,nephron, GWAS ,Single Nucleotide ,1314 Physiology ,medicine.disease ,Claudin ,030104 developmental biology ,Endocrinology ,570 Life sciences ,biology ,Kidney stones ,Human - Abstract
The nature and importance of genetic factors regulating the differential handling of Ca(2+) and Mg(2+) by the renal tubule in the general population are poorly defined. We conducted a genome-wide meta-analysis of urinary magnesium-to-calcium ratio to identify associated common genetic variants. We included 9320 adults of European descent from four genetic isolates and three urban cohorts. Urinary magnesium and calcium concentrations were measured centrally in spot urine, and each study conducted linear regression analysis of urinary magnesium-to-calcium ratio on ~2.5 million single-nucleotide polymorphisms (SNPs) using an additive model. We investigated, in mouse, the renal expression profile of the top candidate gene and its variation upon changes in dietary magnesium. The genome-wide analysis evidenced a top locus (rs172639, p = 1.7 × 10(-12)), encompassing CLDN14, the gene coding for claudin-14, that was genome-wide significant when using urinary magnesium-to-calcium ratio, but not either one taken separately. In mouse, claudin-14 is expressed in the distal nephron segments specifically handling magnesium, and its expression is regulated by chronic changes in dietary magnesium content. A genome-wide approach identified common variants in the CLDN14 gene exerting a robust influence on the differential excretion of Mg(2+) over Ca(2+) in urine. These data highlight the power of urinary electrolyte ratios to unravel genetic determinants of renal tubular function. Coupled with mouse experiments, these results support a major role for claudin-14, a gene associated with kidney stones, in the differential paracellular handling of divalent cations by the renal tubule.
- Published
- 2017
77. Inherited Tubulopathies of the Kidney: Insights from Genetics.
- Author
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Downie ML, Lopez Garcia SC, Kleta R, and Bockenhauer D
- Subjects
- Humans, Kidney physiology, Kidney Diseases genetics, Kidney Tubules
- Abstract
The kidney tubules provide homeostasis by maintaining the external milieu that is critical for proper cellular function. Without homeostasis, there would be no heartbeat, no muscle movement, no thought, sensation, or emotion. The task is achieved by an orchestra of proteins, directly or indirectly involved in the tubular transport of water and solutes. Inherited tubulopathies are characterized by impaired function of one or more of these specific transport molecules. The clinical consequences can range from isolated alterations in the concentration of specific solutes in blood or urine to serious and life-threatening disorders of homeostasis. In this review, we focus on genetic aspects of the tubulopathies and how genetic investigations and kidney physiology have crossfertilized each other and facilitated the identification of these disorders and their molecular basis. In turn, clinical investigations of genetically defined patients have shaped our understanding of kidney physiology., (Copyright © 2021 by the American Society of Nephrology.)
- Published
- 2021
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78. The calcium sensing receptor modulates fluid reabsorption and acid secretion in the proximal tubule
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Peter Geibel, Sara Damiano, Philippe Jaeger, William G. Richards, Giovambattista Capasso, John P. Geibel, Capasso, Giovambattista, Geibel, Pj, Damiano, S, Jaeger, P, Richards, Wg, and Geibel, Jp
- Subjects
Male ,medicine.medical_specialty ,Sodium-Hydrogen Exchangers ,Calcimimetic ,Intracellular pH ,chemistry.chemical_element ,Punctures ,Calcimimetic Agents ,In Vitro Techniques ,Calcium ,Receptors, G-Protein-Coupled ,Kidney Tubules, Proximal ,Rats, Sprague-Dawley ,Mice ,Internal medicine ,Calcium-sensing receptor ,medicine ,Animals ,Kidney stone ,Ion transporter ,Ion transport ,Acid-Base Equilibrium ,Mice, Knockout ,Calcium metabolism ,Kidney tubule ,Reabsorption ,Nuclear Proteins ,Hydrogen-Ion Concentration ,Apical membrane ,Rats ,Cell biology ,Perfusion ,Endocrinology ,chemistry ,Nephrology ,Receptors, Calcium-Sensing ,Transcription Factors - Abstract
The proximal tubule uses a complex process of apical acid secretion and basolateral bicarbonate absorption to regulate both luminal acidification and fluid absorption. One of the primary regulators of apical acid secretion is the luminal sodium–hydrogen exchanger expressed along the apical membrane of the proximal tubule. Similarly, the calcium-sensing receptor (CaSR) is also located along the luminal membrane of the proximal tubule. Here we investigated the role of CaSR in proton secretion and fluid reabsorption in proximal tubules by modulating luminal calcium concentration, using both in vivo micropuncture in rats and in vitro perfused mouse proximal tubules. Using CaSR knockout mice and a calcimimetic agent, we found that increased proton secretion and fluid reabsorption were CaSR dependent. Activating CaSR by either raising the luminal calcium ion concentration or by the calcimimetic caused a concomitant increase in sodium-dependent proton extrusion and fluid reabsorption, whereas in proximal tubules isolated from CaSR knockout mice varying calcium ion concentration had no effect. Application of a calcimimetic in lower concentrations of calcium ion stimulated these processes in vitro and in vivo . Thus, in both rats and mice, increased luminal calcium concentration leads to enhanced fluid reabsorption in the proximal tubule, a process related to activation of CaSR.
- Published
- 2013
79. ACE2 and gut amino acid transport.
- Author
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Camargo SMR, Vuille-Dit-Bille RN, Meier CF, and Verrey F
- Subjects
- Angiotensin-Converting Enzyme 2, Animals, COVID-19, Coronavirus Infections virology, Host-Pathogen Interactions, Humans, Inflammatory Bowel Diseases genetics, Inflammatory Bowel Diseases metabolism, Pandemics, Peptidyl-Dipeptidase A genetics, Pneumonia, Viral virology, Protein Multimerization, SARS-CoV-2, Amino Acid Transport Systems, Neutral metabolism, Betacoronavirus pathogenicity, Coronavirus Infections enzymology, Intestinal Absorption, Intestinal Mucosa enzymology, Membrane Transport Proteins metabolism, Peptidyl-Dipeptidase A metabolism, Pneumonia, Viral enzymology, Virus Internalization
- Abstract
ACE2 is a type I membrane protein with extracellular carboxypeptidase activity displaying a broad tissue distribution with highest expression levels at the brush border membrane (BBM) of small intestine enterocytes and a lower expression in stomach and colon. In small intestinal mucosa, ACE2 mRNA expression appears to increase with age and to display higher levels in patients taking ACE-inhibitors (ACE-I). There, ACE2 protein heterodimerizes with the neutral amino acid transporter Broad neutral Amino acid Transporter 1 (B0AT1) (SLC6A19) or the imino acid transporter Sodium-dependent Imino Transporter 1 (SIT1) (SLC6A20), associations that are required for the surface expression of these transport proteins. These heterodimers can form quaternary structures able to function as binding sites for SARS-CoV-2 spike glycoproteins. The heterodimerization of the carboxypeptidase ACE2 with B0AT1 is suggested to favor the direct supply of substrate amino acids to the transporter, but whether this association impacts the ability of ACE2 to mediate viral infection is not known. B0AT1 mutations cause Hartnup disorder, a condition characterized by neutral aminoaciduria and, in some cases, pellagra-like symptoms, such as photosensitive rash, diarrhea, and cerebellar ataxia. Correspondingly, the lack of ACE2 and the concurrent absence of B0AT1 expression in small intestine causes a decrease in l-tryptophan absorption, niacin deficiency, decreased intestinal antimicrobial peptide production, and increased susceptibility to inflammatory bowel disease (IBD) in mice. Thus, the abundant expression of ACE2 in small intestine and its association with amino acid transporters appears to play a crucial role for the digestion of peptides and the absorption of amino acids and, thereby, for the maintenance of structural and functional gut integrity., (© 2020 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
- Published
- 2020
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80. Cyclodextrins and Congeners in Parenteral Applications
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Pitha, J., Szente, L., and Szejtli, J., editor
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- 1982
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81. Animal Models and Pharmacokinetics
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Mawer, G. E., Williams, J. D., editor, and Geddes, A. M., editor
- Published
- 1976
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82. Mechanism of Morphogenetic Tissue Interactions: The Message of Transfilter Experiments
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Saxén, L., Beermann, W., editor, Gehring, W. J., editor, Gurdon, J. B., editor, Kafatos, F. C., editor, Reinert, J., editor, McKinnell, Robert G., editor, DiBerardino, Marie A., editor, Blumenfeld, Martin, editor, and Bergad, Robert D., editor
- Published
- 1980
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83. Myxozoa, Microspora, and Ascetospora
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Kreier, J. P., Baker, J. R., Kreier, J. P., and Baker, J. R.
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- 1987
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84. A Scanning Electron Microscopy (SEM) Study of the Bladder Mucosa in Paediatric Patients with Idiopathic Calculus Disease
- Author
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Gojaseni, P., Trivitayaratn, C., Sriurairatha, S., Schwille, Paul O., editor, Smith, Lynwood H., editor, Robertson, William G., editor, and Vahlensieck, Winfried, editor
- Published
- 1985
- Full Text
- View/download PDF
85. Active Calcium Transport in Human Red Blood Cells
- Author
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Schatzmann, H. J. and Martonosi, Anthony N., editor
- Published
- 1982
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86. Reduced adenosine uptake and its contribution to signaling that mediates profibrotic activation in renal tubular epithelial cells: Implication in diabetic nephropathy
- Author
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Kretschmar C, Oyarzún C, Villablanca C, Jaramillo C, Alarcón S, Perez G, Díaz-Encarnación MM, Pastor-Anglada M, Garrido W, Quezada C, and San Martín R
- Subjects
Male ,kidney tubule ,Adenosine ,Sprague Dawley rat ,diabetic nephropathy ,fibrosis ,Epithelial Cells ,Rats ,Cell Line ,Rats, Sprague-Dawley ,Kidney Tubules ,Animals ,Humans ,pathology ,animal ,rat ,Diabetic Nephropathies ,human ,epithelium cell ,metabolism ,signal transduction - Abstract
Altered nucleoside levels may be linked to pathogenic signaling through adenosine receptors. We hypothesized that adenosine dysregulation contributes to fibrosis in diabetic kidney disease. Our findings indicate that high glucose levels and experimental diabetes decreased uptake activity through the equilibrative nucleoside transporter 1 (ENT1) in proximal tubule cells. In addition, a correlation between increased plasma content of adenosine and a marker of renal fibrosis in diabetic rats was evidenced. At the cellular level, exposure of HK2 cells to high glucose, TGF-ß and the general adenosine receptor agonist NECA, induced the expression of profibrotic cell activation markers a-SMA and fibronectin. These effects can be avoided by using a selective antagonist of the adenosine A3 receptor subtype in vitro. Furthermore, induction of fibrosis marker a-SMA was prevented by the A3 receptor antagonist in diabetic rat kidneys. In conclusion, we evidenced the contribution of purinergic signaling to renal fibrosis in experimental diabetic nephropathy. Copyright: © 2016 Kretschmar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
- Published
- 2016
87. The uromodulin gene locus shows evidence of pathogen adaptation through human evolution
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Linda Pattini, Peter Vollenweider, Olivier Devuyst, Francesca Tassi, Luca Rampoldi, Guido Barbujani, Silvia Ghirotto, Caroline Hayward, Murielle Bochud, University of Zurich, Rampoldi, L, Ghirotto, S, Tassi, F, Barbujani, G, Pattini, L, Hayward, C, Vollenweider, P, Bochud, M, and Devuyst, O
- Subjects
Genetic Markers ,0301 basic medicine ,Tamm–Horsfall protein ,Population ,030232 urology & nephrology ,Socio-culturale ,610 Medicine & health ,Genome ,10052 Institute of Physiology ,Evolution, Molecular ,03 medical and health sciences ,0302 clinical medicine ,Uromodulin ,Animals ,Humans ,Allele ,education ,Denisovan ,Gene ,Allele frequency ,Genetics ,education.field_of_study ,Urinary tract infection, chronic kidney disease, genetic renal disease, kidney tubule, tubular epithelium ,Urinary tract infection ,2727 Nephrology ,kidney tubule ,biology ,Genetic Variation ,genetic renal disease ,General Medicine ,biology.organism_classification ,030104 developmental biology ,Genetic Loci ,Nephrology ,Urinary Tract Infections ,biology.protein ,570 Life sciences ,Human genome ,tubular epithelium ,chronic kidney disease - Abstract
Common variants in the UMOD gene encoding uromodulin, associated with risk of hypertension and CKD in the general population, increase UMOD expression and urinary excretion of uromodulin, causing salt-sensitive hypertension and renal lesions. To determine the effect of selective pressure on variant frequency, we investigated the allelic frequency of the lead UMOD variant rs4293393 in 156 human populations, in eight ancient human genomes, and in primate genomes. The T allele of rs4293393, associated with CKD risk, has high frequency in most modern populations and was the one detected in primate genomes. In contrast, we identified only the derived, C allele in Denisovan and Neanderthal genomes. The distribution of the UMOD ancestral allele did not follow the ancestral susceptibility model observed for variants associated with salt-sensitive hypertension. Instead, the global frequencies of the UMOD alleles significantly correlated with pathogen diversity (bacteria, helminths) and prevalence of antibiotic-resistant urinary tract infections (UTIs). The inverse correlation found between urinary levels of uromodulin and markers of UTIs in the general population substantiates the link between UMOD variants and protection against UTIs. These data strongly suggest that the UMOD ancestral allele, driving higher urinary excretion of uromodulin, has been kept at a high frequency because of its protective effect against UTIs.
- Published
- 2016
88. Animal Organization as a Problem in Cell Form
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Davison, John, Gregg, John R., editor, and Harris, F. T. C., editor
- Published
- 1964
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89. Identification of the vitamin D receptor in various cells of the mouse kidney
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Megan L. Borchert, Hector F. DeLuca, and Yongji Wang
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Adult ,Male ,medicine.medical_specialty ,Glomerular Mesangial Cell ,Kidney ,Calcitriol receptor ,Kidney Tubules, Proximal ,Mice ,Internal medicine ,medicine ,polycyclic compounds ,Animals ,Humans ,Receptor ,Kidney Tubules, Distal ,Mice, Knockout ,calcium ,kidney tubule ,Reabsorption ,Chemistry ,Podocytes ,urogenital system ,renal cell biology ,Juxtaglomerular apparatus ,Fibroblasts ,Immunohistochemistry ,Juxtaglomerular Apparatus ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Convoluted tubule ,Endocrinology ,Nephrology ,Mesangial Cells ,renal proximal tubule cell ,Macula densa ,Receptors, Calcitriol ,Female ,lipids (amino acids, peptides, and proteins) - Abstract
The kidney is the major, if not sole, site for the production of 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the biologically active form of vitamin D that can stimulate calcium reabsorption in the kidney and may provide renoprotective benefits. The biological effects of 1,25(OH)(2)D(3) are mediated through a nuclear hormone receptor, known as the vitamin D receptor (VDR). It is well accepted that the VDR is present in the distal renal convoluted tubule cells; however, whether VDR is present in other kidney cell types is uncertain. Using a highly specific and sensitive anti-VDR antibody, we determined its distribution in the mouse kidney by immunohistochemistry. Our results show that the VDR is not only present in the distal but is also found in the proximal tubules, but at 24-fold lower levels. The VDR was also found in the macula densa of the juxtaglomerular apparatus, glomerular parietal epithelial cells, and podocytes. In contrast, the VDR is either very low or absent in interstitial fibroblasts, glomerular mesangial cells, and juxtaglomerular cells. Thus, identification of VDR in the proximal tubule, macula densa, and podocytes suggests that 1,25(OH)(2)D(3) plays a direct role in these cells under normal conditions.
- Published
- 2012
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90. The Uromodulin Gene Locus Shows Evidence of Pathogen Adaptation through Human Evolution.
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UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Ghirotto, Silvia, Tassi, Francesca, Barbujani, Guido, Pattini, Linda, Hayward, Caroline, Vollenweider, Peter, Bochud, Murielle, Rampoldi, Luca, Devuyst, Olivier, UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie, Ghirotto, Silvia, Tassi, Francesca, Barbujani, Guido, Pattini, Linda, Hayward, Caroline, Vollenweider, Peter, Bochud, Murielle, Rampoldi, Luca, and Devuyst, Olivier
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Common variants in the UMOD gene encoding uromodulin, associated with risk of hypertension and CKD in the general population, increase UMOD expression and urinary excretion of uromodulin, causing salt-sensitive hypertension and renal lesions. To determine the effect of selective pressure on variant frequency, we investigated the allelic frequency of the lead UMOD variant rs4293393 in 156 human populations, in eight ancient human genomes, and in primate genomes. The T allele of rs4293393, associated with CKD risk, has high frequency in most modern populations and was the one detected in primate genomes. In contrast, we identified only the derived, C allele in Denisovan and Neanderthal genomes. The distribution of the UMOD ancestral allele did not follow the ancestral susceptibility model observed for variants associated with salt-sensitive hypertension. Instead, the global frequencies of the UMOD alleles significantly correlated with pathogen diversity (bacteria, helminths) and prevalence of antibiotic-resistant urinary tract infections (UTIs). The inverse correlation found between urinary levels of uromodulin and markers of UTIs in the general population substantiates the link between UMOD variants and protection against UTIs. These data strongly suggest that the UMOD ancestral allele, driving higher urinary excretion of uromodulin, has been kept at a high frequency because of its protective effect against UTIs.
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- 2016
91. Increased risk of abnormal proximal renal tubular function with HIV infection and antiretroviral therapy
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Fabrice Bonnet, F Dauchy, Claire Rigothier, Carine Greib, Michel Dupon, Sylvie Lawson-Ayayi, Renaud De La Faille, Charles Cazanave, Ghada Miremont-Salamé, François Dabis, and Nadia Mehsen
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Nephrology ,Male ,Time Factors ,Pyridines ,HIV Infections ,Kidney Tubules, Proximal ,Risk Factors ,Antiretroviral Therapy, Highly Active ,Odds Ratio ,Prevalence ,Sida ,biology ,virus diseases ,Middle Aged ,Anti-Retroviral Agents ,Cohort ,Female ,Viral disease ,France ,Oligopeptides ,medicine.drug ,Adult ,medicine.medical_specialty ,antiretroviral therapy ,Atazanavir Sulfate ,Organophosphonates ,Risk Assessment ,Acquired immunodeficiency syndrome (AIDS) ,Internal medicine ,proximal tubule ,medicine ,Humans ,Risk factor ,Tenofovir ,phosphate ,kidney tubule ,business.industry ,Adenine ,HIV ,Odds ratio ,medicine.disease ,biology.organism_classification ,Fanconi Syndrome ,Atazanavir ,Cross-Sectional Studies ,Logistic Models ,Immunology ,HIV-1 ,business - Abstract
Abnormal kidney function is common in the course of human immunodeficiency virus (HIV) infection. Here, we performed a cross-sectional analysis using 399 patients within the Aquitaine cohort (a hospital-based cohort of HIV-1-infected patients receiving routine clinical management) to estimate the prevalence of proximal renal tubular dysfunction (PRTD) associated with HIV infection. These patients did not differ statistically by sociodemographics, median age, years since HIV diagnosis, AIDS stage, or median CD4 cell count from the entire 3080 patient cohort. Antiretroviral therapy was received by 352 patients, with 256 given tenofovir (TDF); 325 had undetectable HIV plasma viral load, and 26 were diagnosed with PRTD. In multivariate analysis, significant independent associations were found between PRTD and age (odds ratio (OR) 1.28 per 5-year increase), atazanavir (OR 1.28 per year of exposure), and TDF (OR 1.23 per year) treatment. Among patients having received TDF-containing regimens over a 5-year period, PRTD remained significantly associated with TDF exposure when treatment was ongoing (OR 5.22) or had been discontinued (OR 11.49). Thus, cumulative exposure to TDF and/or atazanavir was associated with an increased risk of PRTD, with concern about its reversibility in patients with HIV.
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- 2011
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92. The Clinical Significance of Intrarenal Reflux in Voiding Cystourethrography (VCUG)
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Sang Woon Kim, Sang Won Han, Young Jae Im, and Chang Hee Hong
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medicine.medical_specialty ,Kidney tubule ,Pediatric Urology ,business.industry ,Reflux ,Vesico-ureteral reflux ,Radioisotope scanning ,medicine.disease ,urologic and male genital diseases ,Vesicoureteral reflux ,Renal scarring ,Surgery ,Cystourethrography ,Renal injury ,Patient age ,parasitic diseases ,medicine ,Intrarenal reflux ,population characteristics ,Clinical significance ,Original Article ,business - Abstract
Purpose Intrarenal reflux (IRR) occurs in 3-10% of cases of total reflux and can lead to renal injury, which may eventually result in renal scarring. In this study, we evaluated the clinical importance of IRR detected by voiding cystourethrography and evaluated the relationship between IRR and renal scarring. Materials and Methods From January 2002 to May 2008, 50 patients who were diagnosed with vesicoureteral reflux (VUR) and showed IRR in voiding cystourethrography were enrolled. IRR was seen in 59 renal units in our enrolled patients. A 99mTc 2,3-dimercaptosuccinic acid (DMSA) renal scan was performed after VUR was detected in all cases. Nine patients were conservatively treated with prophylactic antibiotics, whereas 41 patients received an anti-reflux operation. A follow-up renal scan was performed after 3 to 6 months to check for any changes in renal scarring. Results The average patient age was 9.2 months (range, 1-42 months). Forty-nine patients were male; only one patient was female. The mean duration until surgery was 2.9 months. Generally, the IRR sites corresponded to the sites of photon defects on DMSA renal scans (76.3%). Furthermore, the photon defects on IRR sites tended to progress to renal scarring (65.2%). The rate of change in scarring was lower in the surgery group (47.1%) than in the prophylactic antibiotic group (75%). Conclusions IRR sites and the sites of photon defects on DMSA renal scans showed a high correspondence, and these sites tended to progress to renal scarring. We suggest that VUR with IRR should be actively managed to decrease the chances of renal scarring.
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- 2010
93. The profiles of biopsy-proven renal tubulointerstitial lesions in patients with glomerular disease.
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Dong J, Li Y, Yue S, Liu X, Wang L, Xiong M, Wang G, Nie S, and Xu X
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Background: Renal tubules and interstitium are vulnerable to injury and play a central role in the progression of various chronic kidney diseases (CKDs). However, high quality epidemiologic study on the profiles of biopsy-proven tubulointerstitial lesions (TILs) is extremely limited., Methods: We conducted a retrospective renal biopsy series including 62,569 native biopsies at 1,211 hospitals across China from 2015 to 2017. The TILs, including the shedding of tube epithelial, renal tubular atrophy, renal interstitial fibrosis, edema and inflammatory infiltration, were identified from the pathological report. We analyzed the severity and chronicity of TILs stratified by gender, age groups, biopsy indications, and concurrent glomerular diseases. We also examined the correlation between TIL and glomerulosclerosis., Results: Of 56,880 patients with biopsy-proven glomerular disease, 79.5% had TILs. Renal interstitial inflammatory infiltration was the most common type of TIL (77.7%), followed by renal tubular atrophy (56.0%) and renal interstitial fibrosis (32.8%). Severe and chronic TILs were more common in adults than in children. The three glomerular diseases with the highest proportion of moderate-to-severe and chronic TIL were diabetic nephropathy, immunoglobulin A (IgA) nephropathy and focal segmental glomerulosclerosis. The severity of TILs was moderately correlated with glomerulosclerosis score (r=0.51). Moderate-to-severe and chronic TIL were more common in southern China. After adjusting for age, sex, hospital level, region, biopsy indication and type of concurrent glomerular diseases, adults with renal arteriole injury had a six-fold higher risk of moderate-to-severe TIL [odds ratio (OR), 7.12; 95% confidence interval (CI), 6.42 to 7.91] and a three-fold higher risk of chronic TIL (OR, 4.58; 95% CI, 4.37 to 4.79)., Conclusions: TILs were common in patients with biopsy-proven glomerular disease. The type and severity of TILs varied with age, region and concurrent glomerular diseases. Renal arteriole injury and glomerulosclerosis was associated with a significantly increased risk of TIL., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-1669). The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)
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- 2020
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94. Quantitative intravital Ca 2+ imaging maps single cell behavior to kidney tubular structure.
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Martins JR, Haenni D, Bugarski M, Figurek A, and Hall AM
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- Acute Kidney Injury metabolism, Animals, Humans, Kidney anatomy & histology, Kidney metabolism, Kidney Tubules, Proximal anatomy & histology, Mice, Calcium metabolism, Calcium Signaling physiology, Kidney Glomerulus metabolism, Kidney Tubules, Proximal metabolism
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Ca
2+ is an important second messenger that translates extracellular stimuli into intracellular responses. Although there has been significant progress in understanding Ca2+ dynamics in organs such as the brain, the nature of Ca2+ signals in the kidney is still poorly understood. Here, we show that by using a genetically expressed highly sensitive reporter (GCaMP6s), it is possible to perform imaging of Ca2+ signals at high resolution in the mouse kidney in vivo. Moreover, by applying machine learning-based automated analysis using a Ca2+ -independent signal, quantitative data can be extracted in an unbiased manner. By projecting the resulting data onto the structure of the kidney, we show that different tubular segments display highly distinct spatiotemporal patterns of Ca2+ signals. Furthermore, we provide evidence that Ca2+ activity in the proximal tubule decreases with increasing distance from the glomerulus. Finally, we demonstrate that substantial changes in intracellular Ca2+ can be detected in proximal tubules in a cisplatin model of acute kidney injury, which can be linked to alterations in cell structure and transport function. In summary, we describe a powerful new tool to investigate how single cell behavior is integrated with whole organ structure and function and how it is altered in disease states relevant to humans.- Published
- 2020
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95. Impaired Renal HCO 3 - Excretion in Cystic Fibrosis.
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Berg P, Svendsen SL, Sorensen MV, Larsen CK, Andersen JF, Jensen-Fangel S, Jeppesen M, Schreiber R, Cabrita I, Kunzelmann K, and Leipziger J
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- Animals, Cyclic AMP physiology, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Cystic Fibrosis Transmembrane Conductance Regulator physiology, Humans, Male, Mice, Mice, Inbred C57BL, Rats, Inbred F344, Receptors, G-Protein-Coupled genetics, Receptors, G-Protein-Coupled physiology, Receptors, Gastrointestinal Hormone genetics, Receptors, Gastrointestinal Hormone physiology, Secretin pharmacology, Bicarbonates metabolism, Cystic Fibrosis metabolism, Kidney metabolism
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Background: Patients with cystic fibrosis (CF) do not respond with increased urinary HCO
3 - excretion after stimulation with secretin and often present with metabolic alkalosis., Methods: By combining RT-PCR, immunohistochemistry, isolated tubule perfusion, in vitro cell studies, and in vivo studies in different mouse models, we elucidated the mechanism of secretin-induced urinary HCO3 - excretion. For CF patients and CF mice, we developed a HCO3 - drinking test to assess the role of the cystic fibrosis transmembrane conductance regulator (CFTR) in urinary HCO3 - excretion and applied it in the patients before and after treatment with the novel CFTR modulator drug, lumacaftor-ivacaftor., Results: β -Intercalated cells express basolateral secretin receptors and apical CFTR and pendrin. In vivo application of secretin induced a marked urinary alkalization, an effect absent in mice lacking pendrin or CFTR. In perfused cortical collecting ducts, secretin stimulated pendrin-dependent Cl- /HCO3 - exchange. In collecting ducts in CFTR knockout mice, baseline pendrin activity was significantly lower and not responsive to secretin. Notably, patients with CF (F508del/F508del) and CF mice showed a greatly attenuated or absent urinary HCO3 - -excreting ability. In patients, treatment with the CFTR modulator drug lumacaftor-ivacaftor increased the renal ability to excrete HCO3 - ., Conclusions: These results define the mechanism of secretin-induced urinary HCO3 - excretion, explain metabolic alkalosis in patients with CF, and suggest feasibility of an in vivo human CF urine test to validate drug efficacy., (Copyright © 2020 by the American Society of Nephrology.)- Published
- 2020
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96. ADPKD, Tolvaptan, and Nephrolithiasis Risk.
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Hoorn EJ and Zietse R
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- Antidiuretic Hormone Receptor Antagonists adverse effects, Humans, Tolvaptan adverse effects, Kidney Calculi, Polycystic Kidney, Autosomal Dominant drug therapy
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- 2020
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97. Quantitative Proteomics of All 14 Renal Tubule Segments in Rat.
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Limbutara K, Chou CL, and Knepper MA
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- Animals, Kidney Tubules metabolism, Male, Rats, Rats, Sprague-Dawley, Transcription Factors analysis, Transcriptome, Kidney Tubules chemistry, Proteomics methods
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Background: Previous research has used RNA sequencing in microdissected kidney tubules or single cells isolated from the kidney to profile gene expression in each type of kidney tubule epithelial cell. However, because proteins, not mRNA molecules, mediate most cellular functions, it is desirable to know the identity and amounts of each protein species to understand function. Recent improvements in the sensitivity of mass spectrometers offered us the ability to quantify the proteins expressed in each of 14 different renal tubule segments from rat., Methods: We manually dissected kidney tubules from rat kidneys and subjected samples to protein mass spectrometry. We used the "proteomic ruler" technique to estimate the number of molecules of each protein per cell., Results: Over the 44 samples analyzed, the average number of quantified proteins per segment was 4234, accounting for at least 99% of protein molecules in each cell. We have made the data publicly available online at the Kidney Tubule Expression Atlas website (https://esbl.nhlbi.nih.gov/KTEA/). Protein abundance along the renal tubule for many commonly studied water and solute transport proteins and metabolic enzymes matched expectations from prior localization studies, demonstrating the overall reliability of the data. The site features a "correlated protein" function, which we used to identify cell type-specific transcription factors expressed along the renal tubule., Conclusions: We identified and quantified proteins expressed in each of the 14 segments of rat kidney tubules and used the proteomic data that we obtained to create an online information resource, the Kidney Tubule Expression Atlas. This resource will allow users throughout the world to browse segment-specific protein expression data and download them for their own research., (Copyright © 2020 by the American Society of Nephrology.)
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- 2020
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98. Mitochondria, mitophagy, and metabolic disease: towards assembling the puzzle.
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Chen Z, Berquez M, and Luciani A
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Dysregulation of the mitochondrial network in terminally differentiated cells contributes to a broad spectrum of disorders. Methylmalonic acidemia (MMA) is an autosomal recessive inborn error of intermediary metabolism caused by the deficiency of methylmalonyl-CoA mutase (MMUT) - a mitochondrial enzyme that mediates the degradation of certain amino acids and lipids. The loss of MMUT activity triggers an accumulation of toxic endogenous metabolites causing severe organ dysfunctions and life-threatening complications. How MMUT deficiency instigates mitochondrial distress and tissue damage remains poorly understood. Using cell and animal-based models, we recently discovered that MMUT deficiency disables the PINK1-induced translocation of PRKN/Parkin to MMA-damaged mitochondria, impeding their delivery and subsequent dismantling by macroautophagy/autophagy-lysosome degradation systems (Luciani et al. Nat Commun . 11(1):970). This promotes an accumulation of damaged and/or dysfunctional mitochondria that spark epithelial distress and tissue damage. Using a systems biology approach based on drug-disease network perturbation modeling, we predicted targetable pathways, whose modulation repairs mitochondrial dysfunctions in patient-derived kidney cells and ameliorates disease-relevant phenotypes in mmut -deficient zebrafish. These results unveil a link between primary MMUT deficiency, defective mitophagy, and cell distress, offering promising therapeutic avenues for MMA and other mitochondria-related diseases., Competing Interests: Conflict of interest: The authors declare no competing interest., (Copyright: © 2020 Chen et al.)
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- 2020
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99. SerpinB2 Regulates Immune Response in Kidney Injury and Aging.
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Sen P, Helmke A, Liao CM, Sörensen-Zender I, Rong S, Bräsen JH, Melk A, Haller H, von Vietinghoff S, and Schmitt R
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- Acute Kidney Injury etiology, Acute Kidney Injury immunology, Animals, Cell Movement, Chemokine CCL2 biosynthesis, Chemokine CCL2 genetics, Coculture Techniques, Enzyme Induction, Epithelial Cells metabolism, Fibrosis, Homeostasis, Kidney blood supply, Kidney pathology, Male, Mice, Mice, Knockout, Phagocytosis, Plasminogen Activator Inhibitor 2 deficiency, Reperfusion Injury immunology, Transcriptome, Ureteral Obstruction enzymology, Ureteral Obstruction immunology, Acute Kidney Injury enzymology, Aging immunology, Cellular Senescence immunology, Kidney enzymology, Kidney Tubules enzymology, Macrophages physiology, Plasminogen Activator Inhibitor 2 physiology, Reperfusion Injury enzymology, Ureteral Obstruction complications
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Background: Expression of SerpinB2, a regulator of inflammatory processes, has been described in the context of macrophage activation and cellular senescence. Given that mechanisms for these processes interact and can shape kidney disease, it seems plausible that SerpinB2 might play a role in renal aging, injury, and repair., Methods: We subjected SerpinB2 knockout mice to ischemia-reperfusion injury or unilateral ureteral obstruction. We performed phagocyte depletion to study SerpinB2's role beyond the effects of macrophages and transplanted bone marrow from knockout mice to wild-type mice and vice versa to dissect cell type-dependent effects. Primary tubular cells and macrophages from SerpinB2 knockout and wild-type mice were used for functional studies and transcriptional profiling., Results: Cultured senescent tubular cells, kidneys of aged mice, and renal stress models exhibited upregulation of SerpinB2 expression. Functionally, lack of SerpinB2 in aged knockout mice had no effect on the magnitude of senescence markers but associated with enhanced kidney damage and fibrosis. In stress models, inflammatory cell infiltration was initially lower in knockout mice but later increased, leading to an accumulation of significantly more macrophages. SerpinB2 knockout tubular cells showed significantly reduced expression of the chemokine CCL2. Macrophages from knockout mice exhibited reduced phagocytosis and enhanced migration. Macrophage depletion and bone marrow transplantation experiments validated the functional relevance of these cell type-specific functions of SerpinB2., Conclusions: SerpinB2 influences tubule-macrophage crosstalk by supporting tubular CCL2 expression and regulating macrophage phagocytosis and migration. In mice, SerpinB2 expression seems to be needed for coordination and timely resolution of inflammation, successful repair, and kidney homeostasis during aging. Implications of SerpinB2 in human kidney disease deserve further exploration., (Copyright © 2020 by the American Society of Nephrology.)
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- 2020
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100. Osmotic water permeability of the apical membrane of proximal straight tubular (PST) cells.
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Gonzáles, Ernesto, Carpi-Medina, Paola, Linares, Henry, and Whittembury, Guillermo
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Osmotic steps, ΔC, were produced across the apical cell membrane of isolated rabbit PST by perfusing their lumens with double barreled micropipettes at a rate of 0.5-0.8 nl/s. ΔC=15-46 mOsmolar were induced with mannitol. Changes in luminal diameter were recorded as a function of time with a TV camera and an integrator-processor system with space and time resolutions of 0.03 μm and 0.0167 s (3). The tubules were bathed with oil. Outer tubule diameter was time invariant. P, the apical cell osmotic permeability was therefore calculated from cell volume changes with time in units of 10 cm/cm. s. Osmolar. P was independent of ΔC. The mean is 22.8±1.3 (n=55). With a basolateral permeability of 50.4 (3,12), the transcellular permeability is 14 (same units) smaller than the transepithelial values available. This leads to the conclusion that a significant paracellular water osmotic permeability must exist. [ABSTRACT FROM AUTHOR]
- Published
- 1984
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