Alterations in renal degradation of albumin in early experimental diabetes in the rat: a new factor in the mechanism of albuminuria

Burne, Melissa J.; Panagiotopoulos, Sianna; Jerums, George; Comper, Wayne D.

doi:10.1042/cs0950067

Cited by 36 publications

(6 citation statements)

References 39 publications

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“…46 HSD-induced tubular proteinuria may have been due to (a) altered retrieval of excess filtered albumin by endocytosis as demonstrated by loss of megalin-cubilin and/or (b) abnormal protein degradation by lysosomes and urine proteases, 53 which return non-immunoreactive peptide fragments of albumin to tubular lumen for excretion that remained undetected by antibodies specific to intact albumin. 54,55 Other tubular protein retrieval mechanisms exist, 56 but how exactly HSD intake in obesity affects these mechanisms is not known. AT 2 R agonist C21 reduced proteinuric indices independent of protein recycling receptors (megalin-cubilin), which suggest that C21 improved either glomerular protein permeability or lysosomal degradation of protein, and thus reduced secretion of nephritic proteins into the tubular lumen.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Type 2–Receptor Agonist C21 Reduces Proteinuria and Oxidative Stress in Kidney of High-Salt–Fed Obese Zucker Rats

2016

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Oxidative and nitrosative stress have been implicated in high sodium diet (HSD)-related hypertensive renal injury. In the present study we investigated AT2R-mediated renoprotection in obese Zucker rats fed HSD. Obese Zucker rats were fed normal sodium-diet (NSD) or HSD 4%, for 14 days, with/without AT2R agonist C21, delivered subcutaneously via osmotic pump, 1 mg/kg/day. Compared to NSD controls, HSD rats exhibited increase in cortical NADPH oxidase activity, urinary H2O2 and 8-isoprostanes, which were associated with severe glomerulosclerosis, interstitial fibrosis, decline in estimated glomerular filtration rate (eGFR), and an increase in urinary leak and activity of N-acetyl-β-D-glucosaminidase, a lysosomal enzyme and a marker of tubular damage. These changes were improved by C21 treatment. Cortical expression of endothelial nitric oxide synthase (eNOS), p-eNOS (Ser1177) and plasma nitrites were reduced after HSD intake while nitrosative stress (3-nitrotyrosine) and enzymatic defense (superoxide dismutase-to-catalase activity) remained unaltered. Albeit, C21 preserved plasma nitrites in HSD-fed OZR. C21 treatment reduced protein-to-creatinine (uPcr), albumin-to-creatinine (uAcr) as well as fractional excretion of protein (FEpro) and albumin (FEalb) in HSD-fed OZR, which is independent of changes in protein recycling receptors, megalin and cubilin. HSD intake also altered renal excretory and reabsorptive capacity as evident by elevated plasma urea nitrogen-to-creatinine (UN-to-cr) and fractional excretion of urea nitrogen (FEUN), and reduced urine-to-plasma creatinine (UPcr), which were modestly, but insignificantly, improved by C21 treatment. Together results demonstrate that AT2R activation protects against HSD-induced kidney damage in obesity plausibly by reducing NOX activity and rescuing nitrites.

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Section: Discussionmentioning

confidence: 99%

Angiotensin II Type 2–Receptor Agonist C21 Reduces Proteinuria and Oxidative Stress in Kidney of High-Salt–Fed Obese Zucker Rats

2016

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“…In fact, some studies have suggested that measurement of urinary albumin by HPLC can predict the onset of overt albuminuria in type 1 and type 2 diabetics 3.9 and 2.4 years earlier, respectively, than a standard immunoassay (12, 14). It has been proposed that the epitopes on the albumin molecule might be altered by conformational changes as a result of incomplete processing by the lysosomal pathway, particularly in early diabetic nephropathy (21, 22). Other studies have suggested that size-exclusion HPLC assay can resolve albumin separately from other proteins of similar molecular size (9).…”

Section: Discussionmentioning

confidence: 99%

Comparison between Immunoturbidimetry, Size-Exclusion Chromatography, and LC-MS to Quantify Urinary Albumin

Shaikh

Seegmiller²,

Borland³

et al. 2008

Clinical Chemistry

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BACKGROUND The accurate and precise measurement of urinary albumin is critical, since even minor increases are diagnostically sensitive indicators of renal disease, cardiovascular events, and risk for death. To gain insights into potential measurement biases, we systematically compared urine albumin measurements performed by LC-MS, a clinically available immunoturbidimetric assay, and size-exclusion HPLC. METHODS We obtained unused clinical urine samples from 150 patients who were stratified by degrees of albuminuria (<20 mg/L, 20–250 mg/L, >250 mg/L) as determined by the immunoturbidimetric assay used in our clinical laboratory (Roche Hitachi 912). Urine albumin was then remeasured via LC-MS and HPLC (Accumin™) assays. RESULTS The immunoturbidimetric assay, calibrated using manufacturer-supplied serum-derived calibrators (Diasorin), underestimated albumin compared with LC-MS. After calibration with purified HSA, this immunoturbidimetric assay correlated well with LC-MS. HPLC overestimated albumin compared with both LC-MS and immunoturbidimetry. The current LC-MS and HPLC assays both performed poorly at concentrations <20 mg/L. CONCLUSIONS Efforts are needed to establish gold-standard traceable calibrators for clinical assays. LC-MS is a specific method to quantify albumin in native urine when concentrations exceed 20 mg/L, and therefore could be employed for standardization among assays.

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“…There is support for this mechanism as both proximal tubule cells [ 8 , 9 , 10 ] and podocytes [ 11 , 12 ] have the ability to endocytose albumin and degrade it through lysosomal activity [ 10 , 11 , 13 ]. It has been known for some time that albumin fragments are excreted in urine in vivo [ 5 , 14 , 15 , 16 , 17 , 18 ] and in urine from the isolated perfused kidney [ 13 , 19 ]; the capacity of this pathway corresponds to a fractional clearance of albumin prior to degradation of ~0.001 in rats [ 6 ]. In albuminuric states albumin fragment excretion is inhibited [ 5 , 6 , 20 , 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the Metabolic Degradation of Filtered Albumin Is a Major Determinant of Albuminuria

Vuchkova

Comper²

2015

PLoS ONE

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Inhibition of the degradation of filtered albumin has been proposed as a widespread, benign form of albuminuria. There have however been recent reports that radiolabeled albumin fragments in urine are not exclusively generated by the kidney and that in albuminuric states albumin fragment excretion is not inhibited. In order to resolve this controversy we have examined the fate of various radiolabeled low molecular weight protein degradation products (LMWDPs) introduced into the circulation in rats. The influence of puromycin aminonucleoside nephrosis on the processing and excretion of LMWDPs is also examined. The status and destinies of radiolabeled LMWDPs in the circulation are complex. A major finding is that LMWDPs are rapidly eliminated from the circulation (>97% in 2 h) but only small quantities (<4%) are excreted in urine. Small (<4%) but significant amounts of LMWDPs may have prolonged elimination (>24 h) due to binding to high molecular weight components in the circulation. If LMWDPs of albumin seen in the urine are produced by extra renal degradation it would require the degradation to far exceed the known catabolic rate of albumin. Alternatively, if an estimate of the role of extra renal degradation is made from the limit of detection of LMWDPs in plasma, then extra renal degradation would only contribute <1% of the total excretion of LMWDPs of albumin. We confirm that the degradation process for albumin is specifically associated with filtered albumin and this is inhibited in albuminuric states. This inhibition is also the primary determinant of the massive change in intact albuminuria in nephrotic states.

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Alterations in renal degradation of albumin in early experimental diabetes in the rat: a new factor in the mechanism of albuminuria

Cited by 36 publications

References 39 publications

Angiotensin II Type 2–Receptor Agonist C21 Reduces Proteinuria and Oxidative Stress in Kidney of High-Salt–Fed Obese Zucker Rats

Angiotensin II Type 2–Receptor Agonist C21 Reduces Proteinuria and Oxidative Stress in Kidney of High-Salt–Fed Obese Zucker Rats

Comparison between Immunoturbidimetry, Size-Exclusion Chromatography, and LC-MS to Quantify Urinary Albumin

Inhibition of the Metabolic Degradation of Filtered Albumin Is a Major Determinant of Albuminuria

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