Molecular mechanisms of proximal tubule cell endocytosis and its pathological roles in the development of chronic kidney disease

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We analyzed molecular mechanisms of functions of megalin, an endocytic receptor in proximal tubule cells. We also established a novel megalin-related method for evaluating chronic kidney disease and investigated megalin-mediated mechanisms of the development of chronic kidney disease.1) We found that megalin and nonmuscle myosin heavy chain IIA interact with the adaptor protein Disabled-2 in proximal tubule cells(Kidney Int 2009).2) Endotoxins are increased in the serum of patients with type 2 diabetes and metabolic syndrome. We found that megalin is downregulated via LPS-TNF-α-ERK1/2 signaling pathway in proximal tubule cells(BBRC 2011).3) We established ELISA systems to measure human megalin and showed that urinary megalin excretion is a useful biomarker for early diagnosis and evaluation of the severity of diabetic nephropathy and for analyzing cardiovascular risks(Diabetes Care 2012).4) We found that liver-derived angiotensinogen is involved in the activation of the renin-angiotensin system(generation of angiotensin II) in the kidney and that glomerular-filtered angiotensinogen is taken up by megalin in proximal tubule cells(JASN 2012).