Evidence of changes in renal charge selectivity in patients with Type 1 (insulin-dependent) diabetes mellitus

Kverneland, A.; Feldt‐Rasmussen, Bo; Vidal, Pablo; Welinder, Benny S.; Bent-Hansen, L.; Søegaard, Ulla; Deckert, T.

doi:10.1007/bf00869262

Cited by 68 publications

(23 citation statements)

References 27 publications

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“…This early excretion of (negatively charged) albumin has been ascribed mainly to loss of anionic sites of the glomerular filtration barrier, according to the so-called Steno hypothesis. Indeed, a decreased selectivity index, i.e., a reduced ratio between (neutral) IgG or (neutral) ␣ 2 -macroglobulin and albumin (negatively charged), has been observed in several studies in microalbuminuric patients (4,12,32) and seems to support the concept of an alteration in the charge barrier. Furthermore, favoring the Steno hypothesis is the finding of a decreased amount of heparan sulfate (HS) side chains of the glomerular basement membrane (GBM) proteoglycans in patients with DNP (36), a decrease that is correlated with the degree of albuminuria (27).…”

Section: Discussionmentioning

confidence: 63%

Size and charge selectivity of the glomerular filter in early experimental diabetes in rats

Rippe¹,

Rippe²,

Torffvit³

et al. 2007

American Journal of Physiology-Renal Physiology

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Rippe C, Rippe A, Torffvit O, Rippe B. Size and charge selectivity of the glomerular filter in early experimental diabetes in rats. Am J Physiol Renal Physiol 293: F1533-F1538, 2007. First published August 15, 2007; doi:10.1152 doi:10. /ajprenal.00271.2007 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 ϳ20 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 () 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. sieving coefficient; proteinuria; capillary permeability; fractional clearance; macromolecules; diabetic nephropathy DIABETIC NEPHROPATHY (DNP) is currently the leading cause of end-stage renal disease in the Western world. In the early course of insulin-dependent diabetes, several functional and structural alterations occur in the kidney. Some of these alterations include glomerular hyperperfusion/hyperfiltration (34), hypertrophy of the nephrons and gross renal enlargement (3,25), and also changes in the glomerular extracellular matrix mass and composition. Microalbuminuria, i.e., moderately increased levels of albumin excretion (20 -200 g/min), is an early sign of DNP, reflecting either alterations in the glomerular barrier to (negatively charged) albumin or a reduction in the protein-reabsorbing properties of the proximal tubules, the latter supported by a recent study (29). According to the "Steno hypothesis," loss of negative charges in the filtration barrier, conceivably due to altered activity of the enzymes involved in the metabolism of extracellular matrix components, may be the cause of the microalbuminuria in early DNP (6). The Steno hypothesis is supported by the preferenti...

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Section: Discussionmentioning

confidence: 63%

Size and charge selectivity of the glomerular filter in early experimental diabetes in rats

Rippe¹,

Rippe²,

Torffvit³

et al. 2007

American Journal of Physiology-Renal Physiology

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“…It is assumed that the loss of negative charges in the basement membrane might be causative for the development of albuminuria (17,18). According to the Steno hypothesis, diabetic complications result from the loss of heparan sulfate proteoglycans in the basement membrane (19).…”

Section: Discussionmentioning

confidence: 99%

Diminished Loss of Proteoglycans and Lack of Albuminuria in Protein Kinase C-α—Deficient Diabetic Mice

et al. 2004

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Activation of protein kinase C (PKC) isoforms has been implicated in the pathogenesis of diabetic nephropathy. We showed earlier that PKC-␣ is activated in the kidneys of hyperglycemic animals. We now used PKC-␣ ؊/؊ mice to test the hypothesis that this PKC isoform mediates streptozotocin-induced diabetic nephropathy. We observed that renal and glomerular hypertrophy was similar in diabetic wild-type and PKC-␣ ؊/؊ mice. However, the development of albuminuria was almost absent in the diabetic PKC-␣ ؊/؊ mice. The hyperglycemia-induced downregulation of the negatively charged basement membrane heparan sulfate proteoglycan perlecan was completely prevented in the PKC-␣ ؊/؊ mice, compared with controls. We then asked whether transforming growth factor-␤1 (TGF-␤ 1 ) and/or vascular endothelial growth factor (VEGF) is implicated in the PKC-␣-mediated changes in the basement membrane. The hyperglycemia-induced expression of VEGF165 and its receptor VEGF receptor II (flk-1) was ameliorated in PKC-␣ ؊/؊ mice, whereas expression of TGF-␤ 1 was not affected by the lack of PKC-␣. Our findings indicate that two important features of diabetic nephropathy-glomerular hypertrophy and albuminuria-are differentially regulated. The glucose-induced albuminuria seems to be mediated by PKC-␣ via downregulation of proteoglycans in the basement membrane and regulation of VEGF expression. Therefore, PKC-␣ is a possible therapeutic target for the prevention of diabetic albuminuria.

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“…Our glycated albumin values for normal subjects are higher than those reported previously, though reported values range widely from 1'5070 to 15% with one exceptional value of 27%. 5 Material in peak II in our chromatography, the glycated albumin fraction, is contaminated with about 10% of the non-glycated form judging from the glycated albumin values measured by radioimmunoassay for glycated protein. This is one of the reasons why our glycated albumin values for normal subjects are high, but the validity of the values measured by various methods has to be evaluated by measuring control samples.…”

Section: Discussionmentioning

confidence: 99%

Serum Glycated Albumin Concentrations during Pregnancy

Abe

Miyamoto

Tahara³

et al. 1993

Ann Clin Biochem

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Additional key phrases: diabetes mellitus; haemoglobin Ale; glycated protein; fructosamineMany studies have been shown that fetal malformation and abnormal growth are significantly increased in pregnancies with poorly-controlled diabetes mellitus and that intensive glycaemic control is required in diabetic pregnancy. 1 Various indices including haemoglobin Ale, glycated protein and fructosamine are reported to be useful for assessing glycaemic control during pregnancy.t-' Glycated protein and fructosamine reflect glycaemic control levels over a shorter period, and so presumably more rapidly, than HbA1c" Measurement of glycated albumin seems more suitable than that of glycated protein because metabolism of serum albumin is better understood than that of other serum proteins. There are many reports of the usefulness of glycated albumin for assessing glycaemic control levels in non-pregnant diabetic patients. However, as there seem to be no reports on its value during pregnancy, we examined the changes of glycated albumin during pregnancy in comparison with those of other measurements. SUBJECTS AND METHODThe subjects studied were 249 pregnant women with normal glucose tolerance before pregnancy. Their fasting plasma glucose, serum total protein (T'P), glycated albumin, fructosarnine, HbA le and urinary glucose concentrations were examined several times between week 10 and 37 of pregnancy. The women were classified into three groups: a normal group, 225 women showed neither glycoCorrespondence: Dr Kenji Shima.198 suria nor hyperglycaemia (fasting glucosẽ 6'1 mmollL) throughout pregnancy; glycosuria group, 13 women who showed glycosuria at least once but not hyperglycaemia; and a hyperglycaernia group, 11 women who showed a fasting glucose concentration of > 6· 1 mmollL at least once. Glycated albumin was measured by column affinity chromatography by the HPLC method described previously. 4 Fructosamine was measured by the nitroblue tetrazolium method with an assay kit from Hoffmann-La Roche Co. (Basle, Switzerland). HbA\c was measured by an HPLC method, and plasma glucose by the international standard method with glucose dehydrogenase. Serum total protein was measured by the biuret method. The coefficients of variation of these assays for glycated albumin, fructosamine, HbA le, plasma glucose and total protein were 3'6,1-7,2-6,2'3 and 0-6l1Jo, respectively. The mean glycated albumin in 153 non-pregnant women aged 18 to 30 (mean 20' 3, SD 2· 5 years) with normal glucose tolerance was 15'6, SD 0·6%.For analysis, data were grouped into three gestational periods (weeks 10-19, 20-29, and 30-37 of gestation) named early, middle and late pregnancy, respectively. Data are given as means (SD). Statistical significance was analysed by ttest for paired and unpaired data or by analysis of variance. RESULTSThe results are summarized in Table 1. In normal pregnant women, fasting plasma glucose and glycated albumin did not change significantly as pregnancy progressed, total protein and fructosamine concentrations were significant...

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Evidence of changes in renal charge selectivity in patients with Type 1 (insulin-dependent) diabetes mellitus

Cited by 68 publications

References 27 publications

Size and charge selectivity of the glomerular filter in early experimental diabetes in rats

Size and charge selectivity of the glomerular filter in early experimental diabetes in rats

Diminished Loss of Proteoglycans and Lack of Albuminuria in Protein Kinase C-α—Deficient Diabetic Mice

Serum Glycated Albumin Concentrations during Pregnancy

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