Blog entry by Meguid El Nahas
ERA-EDTA Congress update:
Searching for molecular mediators
N-acetyl-D-mannosamine could represent a new non immunosuppressive therapeutic agent in the treatment of minimal change nephropathy.
Minimal Change Disease (MCD), Despite being nearly a century old disease, the first molecular mediator behind the structural and functional changes in MCD was only recently discovered. Angiopoietin- like-4 (Angptl4), a glycoprotein secreted from podocytes in large amounts, is now shown to mediate most of the above mentioned characteristic features of MCD. This upregulation in podocytes is glucocorticoid sensitive, and declines with glucocortcoid treatment. it was shown that Angptl4 secreted from podocytes binds to the GBM and induces albuminuria even before the development of foot process effacement.
A precursor of sialic acid, N-acetyl-D-mannosamine (Man- NAc), leads to improved sialylation of podocyte-secreted Angptl4 and significantly reduced proteinuria. ManNAc is relatively non-toxic, and could represent a new non-immunosuppressive therapeutic agent in the treatment of MCD, if shown to be effective in future clinical trials. It is the first potential drug for MCD that primarily affects protein structure, and could be used alone or synergistically with glucocorticoids, that work at least partly by reducing Angptl4 gene upregulation in podocytes.
Treatment with ManNAc improves other parameters of nephrotic syndrome in PAN rats and also reduces proteinuria in Zucker diabetic fatty rats. One important characteristic of the podocyte that favors the further development of ManNAc as a novel therapeutic agent for nephrotic syndrome is its inability to divide. Since ManNAc crosses cell membranes easily and is also rapidly excreted in the urine after an oral or parenteral dose, it is most likely to accumulate in a non-dividing cell like the podocyte even at small doses without significant systemic effects in other organs composed primarily of dividing cells.
In summary, the discovery of Angptl4 may lead the way to future therapeutic approaches for MCD.