Abstract
Microalbuminuria in humans with Type 1 diabetes (T1D) is associated with increased urinary excretion of megalin, as well as many megalin ligands, including vitamin-D-binding protein (VDBP). We examined the DBA/2J diabetic mouse, nephropathy prone model, to determine if megalin and VDBP excretion coincide with the development of diabetic nephropathy. Megalin, VDBP, and 25-hydroxy-vitamin D (25-OHD) were measured in urine, and genes involved in vitamin D metabolism were assessed in renal tissues from diabetic and control mice at 10, 15, and 18 weeks following the onset of diabetes. Megalin, VDBP, and 25-OHD were increased in the urine of diabetic mice. 1-α hydroxylase (CYP27B1) mRNA in the kidney was persistently increased in diabetic mice, as were several vitamin D-target genes. These studies show that intrarenal vitamin D handling is altered in the diabetic kidney, and they suggest that in T1D, urinary losses of VDBP may portend risk for intrarenal and extrarenal vitamin D deficiencies.
Highlights
Abnormal excretion of protein is a clinically relevant indicator of impending diabetes-related renal damage; mechanisms underlying proteinuria in diabetic nephropathy associated with type 1 diabetes mellitus (T1D) are not completely understood
We have recently shown that megalin and cubilin, two multiligand coreceptors expressed in the proximal tubules of the kidney and involved with the reuptake of small-molecular-weight proteins, like albumin, are more abundant in the urine of humans with T1D and microalbuminuria [4]
Megalin and cubilin function as co-receptors involved in the uptake and endocytosis of many small-molecular-weight proteins in the proximal tubule
Summary
Abnormal excretion of protein is a clinically relevant indicator of impending diabetes-related renal damage; mechanisms underlying proteinuria in diabetic nephropathy associated with type 1 diabetes mellitus (T1D) are not completely understood. We have recently shown that megalin and cubilin, two multiligand coreceptors expressed in the proximal tubules of the kidney and involved with the reuptake of small-molecular-weight proteins, like albumin, are more abundant in the urine of humans with T1D and microalbuminuria [4]. Many megalin/cubilin ligands, including vitamin-D-binding protein, are elevated in the urine of these individuals [5]. In support of these findings in humans with T1D, STZinduced T1D in rats results in decreased megalin protein expression along the apical membrane of the proximal convoluted tubules [6]. Loss of megalin/cubilin could contribute to the inability of proximal tubules to adequately reabsorb many filtered proteins in T1D
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