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  • 1
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    Unaltered size selectivity of the glomerular filtration barrier in caveolin-1 knockout mice
    American Physiological Society ; 2009
    In:  American Journal of Physiology-Renal Physiology Vol. 297, No. 2 ( 2009-08), p. F257-F262
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 297, No. 2 ( 2009-08), p. F257-F262
    Abstract: The transfer of albumin from blood to tissue has been found to be increased in caveolin-1 knockout (KO) mice. This has been considered to reflect increased microvascular permeability, conceivably caused by an increased endothelial production of nitric oxide (NO) in these mice. To investigate whether such an increase in NO production would also affect glomerular barrier characteristics, the glomerular sieving coefficients (θ) to neutral FITC-Ficoll 70/400 (molecular radius 13–90 Å) were determined in caveolin-1 KO mice vs. their wild-type counterparts. The θ for Ficoll were assessed using high-performance size-exclusion chromatography on blood and urine samples. Furthermore, the transcapillary escape rate (TER) of 125 I-labeled albumin and plasma volume (PV) were determined in both types of mice. The kidney expressed low levels of caveolin-1 compared with the lung and bladder, but immunofluorescence associated with vascular structures was evident. Staining was lost in the caveolin-1 KO kidney, as was caveolin-1 expression in the lung and bladder. Despite an increase in the glomerular filtration rate in caveolin-1 KO mice (0.23 ± 0.04 vs. 0.10 ± 0.02 ml/min; both n = 7; P 〈 0.05), the glomerular Ficoll sieving curves were nearly identical. Furthermore, caveolin-1 KO mice showed an increased PV (6.59 ± 0.42 vs. 5.18 ± 0.13 ml/100 g; P 〈 0.01) but only a tendency toward an increased TER (14.69 ± 1.59 vs. 11.62 ± 1.62%/h; not significant). It is concluded that in caveolin-1 KO mice the glomerular permeability was not increased, despite the presence of glomerular hyperfiltration. The present data are in line with the concept that the increased transvascular albumin leakage previously found in mice lacking caveolin-1 may be due to an elevation in systemic microvascular pressure due to precapillary vasodilatation, rather than being a consequence of increased microvascular permeability per se.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00075.2009
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2009
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  • 2
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    Transvascular protein transport in mice lacking endothelial caveolae
    American Physiological Society ; 2006
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 291, No. 3 ( 2006-09), p. H1371-H1377
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 291, No. 3 ( 2006-09), p. H1371-H1377
    Abstract: Caveolae are Ω-shaped vesicular structures postulated to play a role in transvascular protein transport. Studies on mice lacking endothelial caveolae, caveolin-1 knockout (Cav-1-KO) mice, indicate increased macromolecular transport rates. This was postulated to be due to the appearance of an alternative pathway. The present study tested whether an alternative pathway had appeared in Cav-1-KO mice. Male Cav-1-KO ( n = 12) and male control mice ( n = 13) were intubated and anesthetized using 2% isoflurane. 125 I-labeled albumin, 131 I-labeled immunoglobulin M (IgM), and polydisperse FITC-Ficoll were administered intravenously. During tracer administration, a 90-min peritoneal dialysis dwell was performed. Clearance of tracers to dialysate and permeability-surface area product for glucose were assessed. Transvascular protein transport was higher in Cav-1-KO compared with control mice. Albumin clearance from plasma to peritoneum was 0.088 ± 0.008 μl/min in control and 0.179 ± 0.012 μl/min in Cav-1-KO ( P = 0.001) mice. IgM clearance was 0.049 ± 0.003 and 0.083 ± 0.010 μl/min in control and Cav-1-KO mice, respectively ( P = 0.016). Ficoll clearance was increased in Cav-1-KO mice. In conclusion, the lack of caveolae in Cav-1-KO mice resulted in a marked increase in macromolecular transport. A two-pore analysis of the Ficoll clearance data revealed that the higher transport rate in Cav-1-KO mice was not compatible with the appearance of an alternative pathway for macromolecular transport. In contrast, the higher transperitoneal protein and Ficoll clearance is consistent with passive porous transport through an unperturbed two-pore system, presumably at an elevated capillary hydraulic pressure. Alternatively, the data may be explained by reductions in the selectivity of the endothelial glycocalyx, leading to an increased capillary hydraulic conductivity and large solute filtration.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.01364.2005
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2006
    detail.hit.zdb_id: 1477308-9
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  • 3
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    Size and charge selectivity of the glomerular filter in early experimental diabetes in rats
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Renal Physiology Vol. 293, No. 5 ( 2007-11), p. F1533-F1538
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 293, No. 5 ( 2007-11), p. F1533-F1538
    Abstract: Microalbuminuria is an early sign of diabetic nephropathy. The aim of the present study was to investigate whether the changes of the glomerular filtration barrier in early experimental diabetes are due to size- or charge-selective alterations. Wistar rats, made diabetic by streptozotocin (STZ) and having their blood glucose maintained at ∼20 mM for 3 or 9 wk, were compared with age-matched controls. Glomerular clearances of native albumin (Cl-HSA) and neutralized albumin (Cl-nHSA) were assessed using a renal uptake technique. Glomerular filtration rate and renal plasma flow were assessed using 51 Cr-EDTA and [ 125 I]iodohippurate, respectively. In a separate set of animals, diabetic for 9 wk, and in controls, glomerular sieving coefficients (θ) for neutral FITC-Ficoll (molecular radius: 15–90 Å) were assessed using size exclusion chromatography. At 3 wk of diabetes, Cl-HSA and Cl-nHSA remained unchanged, indicating no alteration in either size or charge selectivity. By contrast, at 9 wk of diabetes, there was a twofold increase of Cl-HSA, whereas Cl-nHSA remained largely unchanged, at first suggesting a glomerular charge defect. However, according to a two-pore model, the number of large pores, assessed from both Ficoll and Cl-HSA, increased twofold. In addition, a small reduction in proximal tubular reabsorption was observed at 3 wk, which was further reduced at 9 wk. In conclusion, no functional changes were observed in the glomerular filtration barrier at 3 wk of STZ-induced diabetes, whereas at 9 wk there was a decrease in size selectivity due to an increased number of large glomerular pores.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00271.2007
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
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  • 4
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    Arterial remodeling and plasma volume expansion in caveolin-1-deficient mice
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Regulatory, Integrative and Comparative Physiology Vol. 293, No. 3 ( 2007-09), p. R1222-R1231
    Details
    In: American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, American Physiological Society, Vol. 293, No. 3 ( 2007-09), p. R1222-R1231
    Abstract: Caveolin-1 (Cav-1) is essential for the morphology of membrane caveolae and exerts a negative influence on a number of signaling systems, including nitric oxide (NO) production and activity of the MAP kinase cascade. In the vascular system, ablation of caveolin-1 may thus be expected to cause arterial dilatation and increased vessel wall mass (remodeling). This was tested in Cav-1 knockout (KO) mice by a detailed morphometric and functional analysis of mesenteric resistance arteries, shown to lack caveolae. Quantitative morphometry revealed increased media thickness and media-to-lumen ratio in KO. Pressure-induced myogenic tone and flow-induced dilatation were decreased in KO arteries, but both were increased toward wild-type (WT) levels following NO synthase (NOS) inhibition. Isometric force recordings following NOS inhibition showed rightward shifts of passive and active length-force relationships in KO, and the force response to α 1 -adrenergic stimulation was increased. In contrast, media thickness and force response of the aorta were unaltered in KO vs. WT, whereas lumen diameter was increased. Mean arterial blood pressure during isoflurane anesthesia was not different in KO vs. WT, but greater fluctuation in blood pressure over time was noted. Following NOS inhibition, fluctuations disappeared and pressure increased twice as much in KO (38 ± 6%) compared with WT (17 ± 3%). Tracer-dilution experiments showed increased plasma volume in KO. We conclude that NO affects blood pressure more in Cav-1 KO than in WT mice and that restructuring of resistance vessels and an increased responsiveness to adrenergic stimulation compensate for a decreased tone in Cav-1 KO mice.
    Type of Medium: Online Resource
    ISSN: 0363-6119 , 1522-1490
    URL: Article
    DOI: 10.1152/ajpregu.00092.2007
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
    detail.hit.zdb_id: 1477297-8
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  • 5
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    Nature of glomerular capillary permeability changes following acute renal ischemia-reperfusion injury in rats
    American Physiological Society ; 2006
    In:  American Journal of Physiology-Renal Physiology Vol. 291, No. 6 ( 2006-12), p. F1362-F1368
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 291, No. 6 ( 2006-12), p. F1362-F1368
    Abstract: This study was performed to evaluate the alterations of glomerular filtration barrier characteristics following acute renal ischemia-reperfusion (I/R). Ischemia was induced in anesthetized rats by unilateral renal artery occlusion for either 20 or 60 min, followed by reperfusion during 20 or 60 min, respectively, with the contralateral kidney serving as control. Sieving coefficients (θ) were obtained by analyzing Ficoll [mol.radius ( a e ) 13–85 Å] in urine and plasma after 20 and 60 min I/R. Furthermore, θ for human serum albumin (HSA) was estimated using a tissue uptake technique after 20 and 60 min of I/R, while clearance of HSA compared with that for neutralized HSA (nHSA) was assessed after 20 min of I/R only. Glomerular filtration rate (GFR) was measured by [ 51 Cr]EDTA and inulin. I/R reduced GFR and increased θ for Ficoll molecules of a e 〉 55 Å and θ for albumin. θ for Ficoll vs. a e , analysed using a two-pore model, demonstrated that, despite increases in θ, the large-pore fractional ultrafiltration coefficient (α L ) was unchanged after 20 min of I/R, owing to the decline in GFR, but increased after 60 min of I/R. However, the apparent α L for albumin increased already after 20 min of I/R ( P 〈 0.005) and the nHSA/HSA clearance ratio was slightly reduced, possibly reflecting a diminished negative charge barrier. In conclusion, after 20 min of I/R, indications of a reduced charge selectivity were noted, while after 60 min of I/R, there was mainly a reduction in size selectivity, compatible with an increased formation of large pores.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00123.2006
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2006
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  • 6
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    Increased glomerular permeability to negatively charged Ficoll relative to neutral Ficoll in rats
    American Physiological Society ; 2006
    In:  American Journal of Physiology-Renal Physiology Vol. 291, No. 5 ( 2006-11), p. F1083-F1089
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 291, No. 5 ( 2006-11), p. F1083-F1089
    Abstract: It is established that the glomerular filter sieves macromolecules based on their size, shape, and charge. Anionic proteins are thus retarded compared with their neutral or cationic counterparts. However, recent studies have indicated that charge effects are small, or even “anomalous,” for polysaccharides. We therefore investigated the impact of charge on the glomerular permeability to polysaccharides by comparing sieving coefficients (θ; primary urine-to-plasma concentration ratio) for negatively charged, carboxymethylated (CM) FITC-Ficoll and FITC-dextran with their neutral counterparts. For these probes, θ were determined in anesthetized Wistar rats [269 ± 2.7 g (±SE; n = 36)], whose ureters were cannulated for urine sampling. The glomerular filtration rate was assessed using FITC-inulin. Polysaccharides were constantly infused, and after equilibration, urine was collected and a midpoint plasma sample was taken. Size and concentration determinations of the FITC-labeled polysaccharides were achieved by size-exclusion HPLC (HPSEC). For CM-Ficoll, θ was significantly increased (32 times at 55 Å) compared with that of uncharged Ficoll. A small increase in θ for CM-dextran compared with neutral dextran was also observed (1.8 times at 55 Å). In conclusion, negatively charged Ficoll relative to neutral Ficoll was found to be markedly hyperpermeable across the glomerular filter. Furthermore, negatively charged Ficoll was observed to be larger on HPSEC compared with its neutral counterpart of the same molecular weight. It is proposed that the introduction of negative charges in the “dendrimeric,” cross-linked Ficoll molecule may alter its configuration, so as to make it more extended, and conceivably, more flexible, thereby increasing its glomerular permeability.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00488.2005
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2006
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  • 7
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    Glomerular filtration rate dependence of sieving of albumin and some neutral proteins in rat kidneys
    American Physiological Society ; 2003
    In:  American Journal of Physiology-Renal Physiology Vol. 284, No. 6 ( 2003-06-01), p. F1226-F1234
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 284, No. 6 ( 2003-06-01), p. F1226-F1234
    Abstract: The size and charge-selective properties of the glomerular barrier are partly controversial. Glomerular sieving coefficients (θ) for proteins have rarely been determined noninvasively before in vivo. Therefore, θ was assessed vs. glomerular filtration rate (GFR; 51 Cr-EDTA clearance) in intact rats for radiolabeled myoglobin, κ-dimer, neutral horseradish peroxidase (nHRP), neutral human serum albumin (nHSA), and native albumin (HSA). To obtain θ, glomerular tracer clearance, assessed from the 7- to 8-min kidney uptake of protein, was divided by the GFR. The data were fitted with a two-pore model of glomerular permeability, where the small-pore radius was 37.35 ± 1.11 (SE) Å, and the “unrestricted pore area over diffusion path length” ( A 0 /Δ X) 1.84 ± 0.43 · 10 6 cm. Although seemingly horizontal for nHRP and nHSA, the log θ vs. GFR curves showed slightly negative slopes for the proteins investigated in the GFR interval of 2–4.5 ml/min. Strong negative (linear) correlations between (log) θ and GFR were obtained for myoglobin ( P = 0.002) and HSA ( P = 0.006), whereas they were relatively weak for nHRP and nHSA and nonsignificant for κ-dimer. θ for nHSA was markedly higher than that for HSA. In conclusion, there were no indications of increases in θ vs. GFR, as indicative of concentration polarization, for the proteins investigated at high GFRs. Furthermore, the glomerular small-pore radius assessed from endogenous (neutral) protein sieving data was found to be smaller than previously determined using dextran or Ficoll as test molecules.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00316.2002
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2003
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  • 8
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    Loss of size selectivity of the glomerular filtration barrier in rats following laparotomy and muscle trauma
    American Physiological Society ; 2009
    In:  American Journal of Physiology-Renal Physiology Vol. 297, No. 3 ( 2009-09), p. F577-F582
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 297, No. 3 ( 2009-09), p. F577-F582
    Abstract: Posttraumatic microalbuminuria may be caused by either charge- or size-selective alterations in the glomerular filtration barrier, or both, and/or to a reduction in proximal tubular protein reabsorption. This study was performed to elucidate the pathophysiology of the increases in glomerular permeability occurring in rats exposed to a laparotomy or to a laparotomy and muscle trauma. In anesthetized Wistar rats (250–280 g), the left ureter was cannulated for urine collection, while simultaneously blood access was achieved. Rats were exposed to trauma by a laparotomy (L; n = 8), or by a combination of L and muscle trauma (MT; L+MT) induced by topical blunt injury of the abdominal muscles bilaterally. After L, muscles were crushed using hemostatic forceps at either 2 × 2 sites (“small” MT; n = 9), or at 2 × 5 sites (“large” MT; n = 9). Sham groups ( n = 16), not exposed to a laparotomy, were used as controls. The glomerular sieving coefficients (θ) to polydisperse FITC-Ficoll-70/400 (molecular radius 13–80 Å) were determined at 5 or 60 min after L and L+MT, respectively, from plasma and urine samples, and analyzed by high-performance size-exclusion chromatography. A tissue-uptake technique was used to assess θ for 125 I-labeled serum albumin. L, with or without MT, increased θ for Ficoll 55–80Å and albumin rapidly and markedly. θ-Ficoll 70Å thus increased approximately threefold, and θ for albumin significantly, for all trauma groups. According to the “two-pore model” of glomerular permeability, these changes mainly reflect an increase in the number of large pores in the glomerular filter without any primary changes in the charge-selective properties of the filter.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00246.2009
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2009
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  • 9
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    Transient and sustained increases in glomerular permeability following ANP infusion in rats
    American Physiological Society ; 2011
    In:  American Journal of Physiology-Renal Physiology Vol. 300, No. 1 ( 2011-01), p. F24-F30
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 300, No. 1 ( 2011-01), p. F24-F30
    Abstract: The present study was performed to investigate the effects of systemic atrial natriuretic peptide (ANP) infusion on the glomerular permeability to macromolecules in rats. In anesthetized Wistar rats (250–280 g), the left urether was cannulated for urine collection while simultaneously blood access was achieved. Rats were continuously infused intravenously with ANP [30 ng·kg −1 ·min −1 (Lo-ANP; n = 8) or 800 ng·kg −1 ·min −1 (Hi-ANP; n = 10)] or 0.9% NaCl (SHAM; n = 16), respectively, and with polydisperse FITC-Ficoll-70/400 (molecular radius 13–90 Å) and 51 Cr-EDTA for 2 h. Plasma and urine samples were taken at 5, 15, 30, 60, and 120 min of ANP infusion and analyzed by high-performance size-exclusion chromatography (HPLC) for determination of glomerular sieving coefficients (θ) for Ficoll. GFR was also assessed ( 51 Cr-EDTA). In Hi-ANP, there was a rapid (within 5 min), but bimodal, increase in glomerular permeability. θ to high-molecular-weight Ficoll thus reached a maximum at 15 min, after which θ returned to near control at 30 min, to again increase moderately at 60 and 120 min. In Lo-ANP, there was also a rapid, reversible increase in glomerular θ, returning to near control at 30 min, followed by just a tendency of a sustained increase in permeability, but with a significant increase in “large-pore” radius. In conclusion, in Hi-ANP there was a rapid increase in glomerular permeability, with an early, partly reversible permeability peak, followed by a (moderate) sustained increase in permeability. In Lo-ANP animals, only the initial permeability peak was evident. In both Lo-ANP and Hi-ANP, the glomerular sieving pattern observed was found to mainly reflect an increase in the number and radius of large pores in the glomerular filter.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00347.2010
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
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  • 10
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    Reduced diffusion of charge-modified, conformationally intact anionic Ficoll relative to neutral Ficoll across the rat glomerular filtration barrier in vivo
    American Physiological Society ; 2011
    In:  American Journal of Physiology-Renal Physiology Vol. 301, No. 4 ( 2011-10), p. F708-F712
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 301, No. 4 ( 2011-10), p. F708-F712
    Abstract: The glomerular filtration barrier (GFB) is commonly conceived as a negatively charged sieve to proteins. Recent studies, however, indicate that glomerular charge effects are small for anionic, carboxymethylated (CM) dextran vs. neutral dextran. Furthermore, two studies assessing the glomerular sieving coefficients (θ) for negative CM-Ficoll vs. native Ficoll have demonstrated an increased glomerular permeability for CM-Ficoll (Asgeirsson D, Venturoli D, Rippe B, Rippe C. Am J Physiol Renal Physiol 291: F1083–F1089, 2006; Guimarães M, Nikolovski J, Pratt L, Greive K, Comper W. Am Physiol Renal Physiol 285: F1118–F1124, 2003.). The CM-Ficoll used, however, showed a larger Stokes-Einstein radius ( a e ) than neutral Ficoll, and it was proposed that the introduction of negative charges in the Ficoll molecule had made it more flexible and permeable. Recently, a negative FITC-labeled CM-Ficoll (CMI-Ficoll) was produced with a conformation identical to that of neutral FITC-Ficoll. Using these probes, we determined their θ:s in anesthetized Wistar rats (259 ± 2.5 g). After blood access had been achieved, the left ureter was cannulated for urine sampling. Either polysaccharide was infused (iv) together with a filtration marker, and urine and plasma were collected. Assessment of θ FITC-Ficoll was achieved by high-performance size-exclusion chromatography (HPSEC). CMI-Ficoll and native Ficoll had identical elugrams on the HPSEC. Diffusion of anionic Ficoll was significantly reduced compared with that of neutral Ficoll across the GFB for molecules of a e ∼20–35 Å, while there were no charge effects for Ficoll of a e = 35–80 Å. The data are consistent with a charge effect present in “small pores,” but not in “large pores,” of the GFB and mimicked those obtained for anionic membranes in vitro for the same probes.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00183.2011
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
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