Toward understanding renal Fanconi syndrome: step by step advances through experimental models.

Renal Fanconi syndrome (FS) is a generalized dysfunction of proximal tubular epithelial cells leading to the urinary leak of essential metabolites like phosphate, uric acid, glucose, amino acids and low molecular weight proteins. From inherited forms involving mutations on apparently unrelated genes to acquired forms induced by drugs, heavy metals or monoclonal immunoglobulin (Ig) light chains (LC), heterogeneous causalities of FS have complicated the understanding of this pathology for a long time. Experimental models of FS have allowed researchers to face the challenge and have helped unravel the main mechanisms disturbing proximal tubule reabsorption. Administration of cadmium to animals first demonstrated an inhibition of Na/K/ATPase activity, highlighting how a single toxic component could induce the general sodium-linked transport defect observed in FS. Today, genetically modified mice allow the development of reliable and reproducible experimental models for inherited or acquired forms of FS. One of the most exciting advances offered by these models is the unexpected major role of endocytosis in the function of the proximal tubule revealed by megalin and ClC-5 knockout mice. Using gene-targeted insertion, a transgenic mouse for LC-associated FS, the most frequent adult form of FS, has also been recently developed and represents a major step in the development of models of this pathology. Beyond deciphering molecular and cellular events at the origin of FS, these models also represent essential tools for the development of therapeutic strategies.