Role of megalin, a proximal tubular endocytic receptor, in the pathogenesis of diabetic and metabolic syndrome-related nephropathies: protein metabolic overload hypothesis.
Megalin is an endocytic receptor on the apical membranes of proximal tubule cells (PTC) in the kidney, and is involved in the reabsorption and metabolism of various proteins that have been filtered by glomeruli. Patients with diabetes, especially type 2 diabetes, or metabolic syndrome are likely to have elevated serum levels of advanced glycation end products, liver-type fatty acid binding protein, angiotensin II, insulin and leptin, and renal metabolism of these proteins is potentially overloaded. Some of these proteins are themselves nephrotoxic, while others are carriers of nephrotoxic molecules. Megalin is involved in the proximal tubular uptake of these proteins. We hypothesize that megalin-mediated metabolic overload in PTC leads to compensatory cellular hypertrophy and sustained Na+ reabsorption, causing systemic hypertension and glomerular hyperfiltration via tubuloglomerular feedback, and named this as 'protein metabolic overload hypothesis'. Impaired metabolism of bioactive proteins such as angiotensin II and insulin in PTC may enhance hypertrophy of PTC and/or Na+ reabsorption. Sleep apnoea syndrome, a frequent complication of diabetes and metabolic syndrome, may cause renal hypoxia and result in relative overload of protein metabolism in the kidneys. The development of strategies to identify patients with diabetes or metabolic syndrome who are at high risk for renal metabolic overload would allow intensive treatment of these patients in an effort to prevent the development of nephropathy. Further studies on the intracellular molecular signalling associated with megalin-mediated metabolic pathways may lead to the development of novel strategies for the treatment of nephropathies related to diabetes and metabolic syndrome.
Saito
Akihiko
A
Department of Applied Molecular Medicine, Niigata University Graduate School of Medical and Dental Sciences, Asahimachi-dori, Niigata, Japan. akisaito@med.niigata-u.ac.jp
Takeda
Tetsuro
T
Hama
Hitomi
H
Oyama
Yuko
Y
Hosaka
Kiyoko
K
Tanuma
Atsuhito
A
Kaseda
Ryohei
R
Ueno
Mitsuhiro
M
Nishi
Shinichi
S
Ogasawara
Shinya
S
Gondaira
Fumio
F
Suzuki
Yoshiki
Y
Gejyo
Fumitake
F
D003929:Diabetic Neuropathies / Q000209:etiology*; D004705:Endocytosis; D006801:Humans; D007674:Kidney Diseases / Q000209:etiology*; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000378:metabolism*; D024821:Metabolic Syndrome / Q000150:complications*
D026561:Low Density Lipoprotein Receptor-Related Protein-2