Significance of proximal tubular metabolism of advanced glycation end products in kidney diseases.
Advanced glycation end products (AGEs) are formed by the nonenzymatic Maillard reaction between sugars and proteins. Low-molecular weight AGEs are filtered by renal glomeruli and then reabsorbed and metabolized by proximal tubule cells (PTCs). High-molecular weight AGEs are also delivered to PTCs in proteinuric states. In patients with diabetes, AGE generation is increased, and the actions of AGEs on PTCs are likely involved in the pathogenesis of diabetic nephropathy. In patients with chronic renal failure (CRF), reduced renal metabolism of AGEs likely accounts for the accumulation of AGEs in serum, leading to uremic complications including dialysis-related amyloidosis. AGE precursors such as reactive carbonyl compounds also accumulate in the sera of patients with CRF. It is likely that PTCs take up AGEs and AGE precursors via specific endocytotic receptors or transporters. Megalin is a multiligand endocytotic receptor that is abundantly expressed on PTCs. There is evidence that megalin is involved in the cellular uptake and degradation of AGEs. We previously reported a cell therapy model involving implantation of megalin-expressing cells into experimental mice with renal failure for elimination of uremic toxin proteins. Further studies are needed to clarify the molecular mechanisms of the metabolism of AGEs and their precursors to develop a strategy for the treatment of diabetic nephropathy and uremic complications of CRF.
Saito
Akihiko
A
Department of Applied Molecular Medicine, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata, 951-8510, Japan. akisaito@med.niigata-u.ac.jp
Takeda
Tetsuro
T
Sato
Kiyoko
K
Hama
Hitomi
H
Tanuma
Atsuhito
A
Kaseda
Ryohei
R
Suzuki
Yoshiki
Y
Gejyo
Fumitake
F
D003928:Diabetic Nephropathies / Q000378:metabolism*; D004705:Endocytosis; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism*; D007676:Kidney Failure, Chronic / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism; D011507:Proteinuria
D017127:Glycation End Products, Advanced; D026561:Low Density Lipoprotein Receptor-Related Protein-2