Significance of Urinary Full-Length and Ectodomain Forms of Megalin in Patients With Type 2 Diabetes

Ogasawara, Shinya; Hosojima, Michihiro; Kaseda, Ryohei; Kabasawa, Hideyuki; Yamamoto-Kabasawa, Keiko; Kurosawa, Hiroyuki; Sato, Hiroyoshi; Iino, Noriaki; Takeda, Takeshi; Suzuki, Yuichi; Narita, Ichiei; Yamagata, Kunihiro; Tomino, Yasuhiko; Gejyo, Fumitake; Hirayama, Yoshiaki; Sekine, Sakari; Saito, Akihiko

doi:10.2337/dc11-1684

Cited by 56 publications

(84 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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. These reports suggest that increases in urinary cystatin C excretion in diabetic patients may be one of the mechanisms involved in the dissociation of eGFR cys and C in .…”

Section: Discussionmentioning

confidence: 97%

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

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 97%

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

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Megalin and cubilin function together in the reabsorption of proteins, including IgG and albumin, in the proximal tubule (43,44). Impairment of megalin function in diabetes has been suggested, even in the early stages of diabetes in animal models and in patients (45). Megalin expression can be severely downregulated due to protein over-load in diabetes, via activation of the renin-angiotensin system and increased TGF-β and TNF-α signaling in the lumen of the proximal tubular cells (46).…”

Section: Discussionmentioning

confidence: 99%

Effect of Type 2 Diabetes Mellitus and Diabetic Nephropathy on IgG Pharmacokinetics and Subcutaneous Bioavailability in the Rat

Chadha

Morris

2015

AAPS J

View full text Add to dashboard Cite

Abstract. The objective of this research was to assess the effects of type 2 diabetes mellitus (T2DM) and diabetic nephropathy (DN) on the pharmacokinetics of human IgG (hIgG), an antibody isotype, in Zucker diabetic fatty (ZDF) rats. Furthermore, the specific role of T2DM in the altered disposition of hIgG was evaluated by treating diabetic rats with pioglitazone, while the role of chronic kidney disease (CKD) was assessed using 5/6 nephrectomized Sprague Dawley rats. ZDF male (lean non-diabetic control and obese diabetic) and pioglitazone-treated ZDF rats were studied at ages 12-13 weeks (only DM was present), and at ages 29-30 weeks (progression to DN). All animals were dosed with 1 mg/kg of hIgG intravenously (IV) or subcutaneously (SC). ZDF rats had significantly higher blood glucose concentrations and urinary albumin excretion compared to control rats. Significant increases in total clearance (2.5-fold) and renal clearance (100-fold) of hIgG were observed; however the major increase in total clearance was due to increased non-renal clearance. Greater changes in urinary albumin excretion and total and renal clearances of IgG (3.5-fold and 300-fold, respectively) were observed with progression to DN. SC bioavailability of hIgG in all animal groups was similar (>84%). With pioglitazone-treatment, diabetic animals remained euglycemic and treatment was able to reverse the clearance changes, although incompletely. In the CKD group, no difference in hIgG clearance was observed when compared with controls. In conclusion, the increased clearance of hIgG in ZDF diabetic animals, reversal by pioglitazone treatment and lack of effect of CKD, demonstrate the influence of T2DM on hIgG pharmacokinetics.

show abstract

“…Quantification of urinary A-megalin and C-megalin was performed as previously described [21, 22]. In brief, 90-µL urine samples were mixed with a 10-µL solution (2 mol/L Tris-HCl, 0.2 mol/L EDTA, 10% Triton X-100, pH 8.0), and incubated for 1 min at room temperature for the C-megalin assay and for 3 h at 50°C for the A-megalin assay, to allow reactions between the capture monoclonal antibodies immobilized on the ELISA plates and the carboxy- and amino-terminal portions of megalin, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…The intra- and inter-assay coefficients of variation were less than 10%. Urinary concentrations of Cr, N-acetyl-β-D-glucosaminidase (NAG), and β 2 -microglobulin were measured using an automated instrument (7170S; Hitachi High-Technologies Corp., Tokyo, Japan) with CRE-S (Denka Seiken Co., Ltd., Gosen, Japan), N-assay L NAG NITTOBO (Nittobo Medical Co., Ltd., Tokyo, Japan), and BMG-Latex (Denka Seiken Co., Ltd., Gosen, Jappan) kits, respectively, as previously described [21]. As a marker for oxidative stress in urine, urinary 8-OHdG was measured by ELISA (Japan Institute for the Control of Aging, NIKKEN SEIL, Co., Ltd., Shizuoka, Japan), as previously described [28].…”

Section: Methodsmentioning

confidence: 99%

“…Recently, sandwich enzyme-linked immunosorbent assays (ELISAs) have been developed that are able to more precisely quantify ectodomain (A-megalin) and full-length (C-megalin) forms of megalin using monoclonal antibodies against the amino- and carboxyl-terminal of megalin, respectively [21]. Using these assays, urinary C-megalin/Cr levels were found to be elevated even in the normoalbuminuric stage of type 2 diabetes and increased further in conjunction with progression of diabetic nephropathy in those patients [21]. In addition, urinary C-megalin/Cr was reportedly associated with the severity of IgA nephropathy [22] and pediatric renal scarring [23].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Urinary Iron Excretion is Associated with Urinary Full-Length Megalin and Renal Oxidative Stress in Chronic Kidney Disease

Nakatani

Ishimura

et al. 2018

Kidney Blood Press Res

Self Cite

View full text Add to dashboard Cite

Background/Aims: Megalin mediates the uptake of glomerular-filtered iron in the proximal tubules. Urinary full length megalin (C-megalin) excretion has been found to be increased in association with megalin-mediated metabolic load to the endo-lysosomal system in proximal tubular epithelial cells (PTECs) of residual nephrons. In the present study, we investigated the association between urinary iron and C-megalin in chronic kidney disease (CKD) patients, and the possible harmful effect of iron in renal tubules. Methods: Urinary levels of iron and C-megalin were measured in 63 CKD patients using automatic absorption spectrometry and a recently-established sandwich ELISA, respectively. Results: Although both urinary C-megalin and urinary total protein levels were correlated with urinary iron (C-megalin: ρ = 0.574, p <0.001; total protein: ρ = 0.500, p <0.001, respectively), urinary C-megalin alone emerged as an independent factor positively associated with urinary iron (β = 0.520, p <0.001) (R² = 0.75, p <0.001). Furthermore, urinary iron was significantly and positively associated with urinary 8-hydroxydeoxyguanosine, an oxidative stress marker, while no association with other markers of renal tubular injury, i.e., β₂-microglobulin and N-acetyl-β-D-glucosaminidase, was noted. Conclusions: Our findings suggest that renal iron handling may be associated with megalin-mediated endo-lysosomal metabolic load in PTECs of residual nephrons and oxidative stress in renal tubules.

show abstract

Significance of Urinary Full-Length and Ectodomain Forms of Megalin in Patients With Type 2 Diabetes

Cited by 56 publications

References 42 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

Effect of Type 2 Diabetes Mellitus and Diabetic Nephropathy on IgG Pharmacokinetics and Subcutaneous Bioavailability in the Rat

Urinary Iron Excretion is Associated with Urinary Full-Length Megalin and Renal Oxidative Stress in Chronic Kidney Disease

Contact Info

Product

Resources

About