Physiological importance of endosomal acidification: potential role in proximal tubulopathies

In recent years, there have been significant advances in our understanding of the molecular mechanisms relating proximal tubule abnormalities to the pathogenesis of renal Fanconi syndrome. This review focuses on the role of intra-endosomal acidification-machinery proteins (V-ATPase, CLC-5, NHE-3), as well as apical receptors (megalin and cubilin), in the receptor-mediated endocytosis pathway and in the pathogenesis of proximal tubulopathies.

Animal models, including CLC-5 and megalin knockout mice, cubilin-deficient dogs and cadmium-toxicity studies in rats, have shed light on defects leading to low-molecular-weight proteinuria. In particular, the important contribution of defective endosomal acidification and membrane-protein recycling to the pathogenesis of the Fanconi syndrome has emerged from these studies. These observations, together with recent findings in patients with Dent's disease, Lowe's syndrome, autosomal-dominant idiopathic Fanconi syndrome and Imerslund-Grasbeck disease, show that the proteinuria of the Fanconi syndrome is more generalized than previously suspected. High concentrations of polypeptides, including hormones, vitamin-binding proteins and chemokines in urine from these patients and animals may play an important role in the progressive renal failure that is associated with the syndrome.

The molecular mechanism of proximal tubule protein reabsorption, which is defective in renal Fanconi syndrome, includes a crucial role for endosomal acidification-machinery proteins, in particular the V-ATPase and CLC-5 chloride channels, in the trafficking and acidification-dependent recycling of apical membrane proteins, including the endocytotic receptors megalin and cubilin. An increased understanding of the roles of V-ATPase and CLC-5 in proximal tubule endosomal acidification, in the regulation of the megalin/cubilin-mediated endocytosis pathway and finally in the pathogenesis of human Fanconi syndrome will help in the devising of appropriate strategies for therapeutic intervention for this disorder.