Abstract
The most important thing on treating glomerular disease is to prevent deterioration of kidney function. It is previously shown that prognosis of kidney function depends on the dose of proteinuria. Moreover, the risk to be end stage renal failure will get serious, if high molecular weight proteins are included in proteinuria.
A portion of proteins filtered through glomeruli are reabsorbed to proximal tubule cells (PTCs) by endocytosis. The most important receptor of PTCs related to endocytosis is megalin, which exists on apical membrane of PTCs. There are many kinds of protein which are established to be ligands of megalin. Some of the ligands are vitamin-binding proteins, carrier proteins, lipoproteins, hormones, hormone precursors, enzymes, enzyme inhibitors and immune- and stress- response-related proteins. A part of the proteins are transported to lysosome after reabsorption to PTC and degraded. Others are transported from apical membrane to basolateral membrane through PTC without degradation.
When glomerular diseases occur, not only low to intermediate proteins but also high molecular weight proteins are filtered through glomeruli. Utilizing kidney-specific megalin knockout mice, we have shown that high molecular weight proteins, namely IgG and IgA, are reabsorbed to PTCs by mediation of megalin. When large amount of proteins is overloaded to PTCs, mediators which are related to inflammation and fibrosis, namely monocyte chemoattractant protein-1, RANTES, interleukin-8, fractalkine, tumor necrosis factor-α, endothelin, and transforming growth factor-β, are released by PTCs to tubulointerstitial area. The release of mediators is considered as beginning of tubule injury and interstitial fibrosis. Apoptosis of PTCs are also induced after protein overload to the cells.
In spite of previous exertions done by many researchers, there are many ambiguous points left to elucidate the process of deterioration of kidney function. However, we consider that direct damage of PTCs induced by reabsorbed proteins might cause a vicious circle and take much part in progression to end stage renal disease.
