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Role of megalin, a proximal tubular endocytic receptor, in the pathogenesis of diabetic and metabolic syndrome-related nephropathies: protein metabolic overload hypothesis (2005)

SAITO, AKIHIKO ; TAKEDA, TETSURO ; HAMA, HITOMI ; [et al.]

Melbourne, Australia : Blackwell Science Pty

Nephrology 10 (2005), S. 0

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ISSN: 1440-1797

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Medicine

Notes: SUMMARY: 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.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1111/j.1440-1797.2005.00453.x

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Comparison of penetration-enhancing ability of laurocapram, N-methyl-2-pyrrolidone and dodecyl-L-pyroglutamate (1988)

Příborský, Jan ; Takayama, Kozo ; Nagai, Tsuneji ; [et al.]

Springer

Pharmacy world & science 10 (1988), S. 189-192

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ISSN: 1573-739X

Keywords: Absorption, transdermal ; Brilliant Blue ; Dodecyl-l-pyroglutamate ; Insulin ; Laurocapram ; N-Methyl-2-pyrrolidone ; Permeability, enhancement

Source: Springer Online Journal Archives 1860-2000

Topics: Chemistry and Pharmacology

Notes: Abstract The study reports on penetration enhancers used to improve drug absorption through the skin. All experiments were carried out in permeation cellsin vitro. Insulin (2.5 mg/ml) and Brilliant Blue (50.0 mg/ml) served as model drugs. They were formulated into a 40% solution of propylene glycol with increasing concentrations ofN-methyl-2-pyrrolidone (NMP) (0.0 to 20.0%), dodecylazacycloheptan-2-one (laurocapram) and a new compound dodecyl-l-pyroglutamate (DLP; 0.0 to 0.5%). The maximum amount of insulin permeated within 24 h was almost 200 μU/ml in the case of 0.1% laurocapram, while in the case of 0.1% DLP it was approximately half of that. The optimum concentration of NMP was 12.0%. Experiments performed with Brilliant Blue showed no significant difference among formulations containing either 6.0, 12.0 or 20.0% of NMP. When NMP was omitted, flux, permeability as well as the maximum concentration estimated after 26 h reached 50% of the values obtained with NMP. The lag time was twice as long in this case in comparison with the formulations containing NMP.