Dent disease, is a disorder that is characterized by low molecular weight proteinuria, aminoaciduria, glycosuria, hyperphosphaturia (Fanconi syndrome) loss of sodium and water as well as hypercalciuria, nephrocalcinosis, and nephrolithiasis. Dent disease has been established to be caused by mutations of the CICN-5 gene, the product of which is CIC-5 voltage-gated Cl/H exchanger expressed in highest abundance in renal tubules ofthe proximal nephron. Our preliminary studies in a CICn-5 knockout mouse model, show that it recapitulates the features of Dent disease including low molecular weight proteinuria, aminoaciduria, glycosuria, loss of sodium, polyuria, hyperphosphaturia, hypercalciuria, renal calcifications, and renal failure. The proposed study will define the underlying molecular basis of these reabsorption defects. Our studies have shown CIC-5 Is necessary for exocytosis of NHE3 under basal and stimulated conditions.
Specific aim 1. We hypothesize that loss of Clc-5 or an alkaline pH In the recycling endosome causes decreased exocytic trafficking of NHES and less surface NHES. Total NHES is not reduced because synthesis and surface delivery of NHES does not occur via the recycling endosome and is normal.
Specific aim 2. We hypothesize that surface megalin in CICn-5 ko proximal tubules is decreased because megalin Is arrested in the recycling endosome when CIC-5 is lacking, or there is an alkaline pH in this compartment. Another option that may alter megalin at the surface is decreased surface NHES activity. We hypothesize that the loss of CIC-5, or increased endosomal pH causes less synthesis and apical delivery of megalin because this process occurs through the recycling endosome.
Specific aim S. We hypothesize that the loss of CIC-5, or Increased endosomal pH causes less synthesis and delivery of newly synthesized Npt2a to the surface because this process occurs via a CIC-5 positive compartment.

Public Health Relevance

This grant will outline the molecular mechanisms underlying the kidney defects in Dent disease. The outcome of this disease Is loss of important nutrients Including proteins, sodium and phosphate. This disease also causes painful kidney stones and kidney failure. In order to treat any of these outcomes of this disease we need to know more about how the faulty movement of key proteins are caused.

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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