Albumin filtered in the renal glomerulus is reabsorbed by renal epithelial cells in the proximal tubule through a process of receptor-mediated endocytosis. Various renal diseases are associated with increased glomerular albumin filtration, which leads to increased proximal tubule albumin and the appearance of albumin in the urine (albuminuria), which, in turn, contribute to the progression of renal dysfunction. Peruchetti et al. used the LLC-PK1 line of polarized pig renal epithelial cells as a model of proximal tubule cells in which to explore the effects of physiological and pathophysiological concentrations of albumin on the Na,K-ATPase, or sodium pump, an enzyme crucial for renal sodium reabsorption. Albumin at concentrations between 0.0005 and 1.0 mg/ml increased LLC-PK1 Na,K-ATPase activity, an effect that peaked at 0.01 mg/ml albumin and then decreased, so that 10 or 20 mg/ml albumin failed to stimulate pump activity. When added to the luminal surface where it is endocytosed, albumin stimulated Na,K-ATPase activity; however, albumin did not affect Na,K-ATPase activity when added to the basolateral side where the Na,K-ATPase is located. Albumin’s stimulation of Na,K-ATPase activity became apparent after 2 hours of exposure, and pharmacological analysis indicated that it depended on protein synthesis; a combination of approaches indicated that 0.01 mg/ml albumin increased the abundance of the Na,K-ATPase α1 subunit in cell homogenates and at the basolateral cell surface. Albumin applied at 0.01 mg/ml increased the activity of protein kinase C (PKC) and decreased that of protein kinase A (PKA), whereas 20 mg/ml albumin decreased PKC activity and had no effect on that of PKA. Pharmacological analysis indicated that albumin’s activation of PKC and Na,K-ATPase depended on phosphatidylinositol 3-kinase (PI3K)–protein kinase B (PKB, also known as Akt) signaling and that inhibition of PKA through PI3K-PKB-PKC signaling contributed to its enhancement of Na,K-ATPase activity. The authors thus propose that endocytosed albumin acts as a messenger to modulate intracellular pathways that regulate Na,K-ATPase abundance and thereby sodium reabsorption in the proximal tubule.
D. B. Peruchetti, A. A. S. Pinheiro, S. S. Landgraf, M. Wengert, C. M. Takiya, W. B. Guggino, C. Caruso-Neves, (Na+ + K+)-ATPase is a target for phosphoinositide 3-kinase/protein kinase B and protein kinase C pathways triggered by albumin. J Biol. Chem. 286, 45041-45047 (2011). [Abstract] [Full Text]