Megalin-mediated endocytosis of cystatin C in proximal tubule cells

Kaseda, Ryohei; Iino, Noriaki; Hosojima, Michihiro; Takeda, Takeshi; Hosaka, Kiyoko; Kobayashi, Asako; Yamamoto, Keiko; Suzuki, Akihiro; Kasai, Ayaka; Suzuki, Yuichi; Gejyo, Fumitake; Saito, Akihiko

doi:10.1016/j.bbrc.2007.04.072

Cited by 81 publications

(57 citation statements)

References 31 publications

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“…Secondly, although the higher eGFR cr in diabetic patients was suggested to be caused by tubular creatinine secretion, we could not determine the mechanism of overestimation of the renal function in the diabetic patients when it was estimated by eGFR cys , since we were not able to measure urine cystatin C. However, it has been reported that urinary cystatin C appears even before the increase in the classical biomarkers of diabetic nephropathy, such as albuminuria and urinary protein (36). It has also been reported that cystatin C is filtered by glomeruli and metabolized in proximal tubular cells by binding to megalin in a Ca 2+ -dependent manner (14). Ogasawara et al (37) reported that urinary megalin was increased in correlation with the severity of type 2 diabetic nephropathy, likely leading to reduced metabolism of cystatin C in tubuli.…”

Section: Discussionmentioning

confidence: 99%

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Poor Glycemic Control Is a Major Factor in the Overestimation of Glomerular Filtration Rate in Diabetic Patients

et al. 2014

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OBJECTIVESerum creatinine levels are lower in diabetic patients compared with their nondiabetic counterparts. Therefore, estimated glomerular filtration rate (eGFR) is higher in the former than in the latter group. Factors associated with overestimation of renal function in diabetic patients were examined, and new formulae reflecting precise eGFR were created. RESEARCH DESIGN AND METHODSEighty subjects (age 56.5 6 15.4 years; 35 males [43.8%]; 40 patients with diabetes and 40 nondiabetic subjects) were enrolled. GFR was evaluated by inulin clearance (C in ). eGFR values were calculated based on serum creatinine and/or serum cystatin C levels. The factors related to the dissociation between eGFR and C in in diabetic patients and the agreement among each of three eGFR and C in were compared. RESULTSAlthough C in was not significantly different between the diabetic and nondiabetic subjects (P = 0.2866), each of three eGFR measures from the diabetic patients was significantly higher than that of the nondiabetic subjects (P < 0.01). There were significant and positive correlations between the ratio of each eGFR/ C in , hemoglobin A 1c , and glycated albumin. The intraclass correlation coefficients in diabetic patients were weaker than those in the nondiabetic subjects, and the intercepts of the regression lines between each eGFR measure and C in in the diabetic patients were significantly higher than those of the nondiabetic subjects. New formulae for the calculation of eGFR corrected by the glycemic control indices were better than the original eGFR, particularly in diabetic patients. CONCLUSIONSeGFR overestimates C in as glycemic controls worsen. eGFR corrected by hemoglobin A 1c is considered to be clinically useful and feasible.

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Section: Discussionmentioning

confidence: 99%

“…It is known that cystatin C is filtered by the glomeruli and metabolized in proximal tubular cells by Megalin in a Ca 2+ -dependent manner (14). Cystatin C is not affected by muscle mass, sex, or age.…”

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confidence: 99%

Poor Glycemic Control Is a Major Factor in the Overestimation of Glomerular Filtration Rate in Diabetic Patients

et al. 2014

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“…In the kidney, there are receptors and transporters such as sodium/glucose co-transporter-2 and organic cation transporter 2, which have been reported that testosterone changed their expression levels in rats (Pávó et al, 1995;Urakami et al, 2000;Ljubojevic et al, 2004;Sabolic et al, 2012;Loh et al, 2017). Meanwhile, sex differences of megalin and cubilin, receptors related to reabsorption of LMWPs and albumin which are localized in the renal proximal tubules (Cui et al, 1996;Orlando et al, 1998;Birn et al, 2000;Oyama et al, 2005;Hvidberg et al, 2005;Kaseda et al, 2007;Amsellem et al, 2010), have been ambiguous. It might be possible that one or more receptors and transporters contributing to reabsorption of LMWPs and albumin were affected by testosterone, and their excretion levels had varied.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in the excretion levels of traditional and novel urinary biomarkers of nephrotoxicity in rats

et al. 2017

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-Urinary biomarkers have been used widely in preclinical toxicity studies to detect dysfunctions and injuries of the kidney caused by drugs under development. While they have been well studied for evaluating nephrotoxicity, knowledge of sex differences in excretion levels of urinary biomarkers remains inadequate. We conducted experiments focused on effects of endogenous sex hormones on urinary biomarkers using intact and castrated male and female rats. Comparisons of the urinary biomarker excretion levels between intact male and female rats at 5, 7, 9 and 12 weeks of age revealed higher excretion levels of leucine aminopeptidase (LAP), γ-glutamyl transpeptidase (γGTP), total protein, liver-type fatty acid-binding protein (L-FABP), cystatin C (Cys-C) and β2-microglobulin (β2-MG), and lower excretion level of kidney injury molecule 1 (Kim-1), in male rats as compared to female rats. Orchidectomized male rats showed lower urinary excretion levels of alkaline phosphatase (ALP), LAP, γGTP, N-acetyl-β-D-glucosaminidase (NAG), glucose, total protein, L-FABP, Cys-C, β2-MG and neutrophil gelatinaseassociated lipocalin (NGAL), and higher urinary excretion levels of clusterin (CLU) and Kim-1, than sham-operated male rats. On the other hand, no significant differences in the urinary biomarker excretion levels excluding ALP were observed between ovariectomized and sham-operated female rats. In the present study, we demonstrated the existence of sex differences in excretion levels of urinary biomarkers that are universally used in preclinical toxicity studies, and also that these differences, especially in relation to the urinary excretions of ALP, LAP, γGTP, total protein, L-FABP, Cys-C, and β2-MG, may closely relate to the endogenous testosterone.

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“…After being filtered without restriction by the glomeruli because of its low molecular mass and absence of protein binding, CysC is entirely reabsorbed by the proximal tubules, where it is almost entirely catabolised (26,27,69). Tubular reabsorption occurs through a receptor, megalin (common to many proteins including albumin) by endocytosis (70)(71)(72). It is widely accepted that no tubular secretion of CysC occurs, although one study in human beings published data which may suggest the opposite (73).…”

Section: What Is the Renal Fate Of Cysc?mentioning

confidence: 99%

Cystatin C: current position and future prospects

Séronie-Vivien

Delanaye

Piéroni³

et al. 2008

Clinical Chemistry and Laboratory Medicine

164

145

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Cystatin C is a low-molecular-weight protein which has been proposed as a marker of renal function that could replace creatinine. Indeed, the concentration of cystatin C is mainly determined by glomerular filtration and is particularly of interest in clinical settings where the relationship between creatinine production and muscle mass impairs the clinical performance of creatinine. Since the last decade, numerous studies have evaluated its potential use in measuring renal function in various populations. More recently, other potential developments for its clinical use have emerged. This review summarises current knowledge about the physiology of cystatin C and about its use as a renal marker, either alone or in equations developed to estimate the glomerular filtration rate. This paper also reviews recent data about the other applications of cystatin C, particularly in cardiology, oncology and clinical pharmacology. Clin Chem Lab Med 2008;46:1664-86.

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Megalin-mediated endocytosis of cystatin C in proximal tubule cells

Cited by 81 publications

References 31 publications

Poor Glycemic Control Is a Major Factor in the Overestimation of Glomerular Filtration Rate in Diabetic Patients

Poor Glycemic Control Is a Major Factor in the Overestimation of Glomerular Filtration Rate in Diabetic Patients

Sex differences in the excretion levels of traditional and novel urinary biomarkers of nephrotoxicity in rats

Cystatin C: current position and future prospects

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