The present proposal is for continuation of a longstanding research program that had originally been directed at studying the ion exchangers mediating acid-base and NaCl transport in the proximal tubule. In the course of this work the applicants cloned and characterized a novel transporter expressed on the apical membrane of proximal tubule cells, SLC26A6. They showed that SLC26A6 is capable of mediating Cl- formate and Cl-oxalate exchange, and generated Slc26a6-null mice to evaluate its role in proximal tubule NaCl transport. However, they unexpectedly observed a striking phenotype of calcium oxalate urolithiasis due to hyperoxaluria. They found that the cause of the hyperoxaluria is increased net absorption of dietary oxalate due to a defect in SLC26A6-mediated oxalate secretion in the intestine. In addition, work by others indicated that a defect in SLC26A1-mediated oxalate transport could also result in calcium oxalate urolithiasis. The research program was therefore re-directed to focus on the roles of SLC26A6 and SLC26A1 in oxalate homeostasis and hyperoxaluria. The apical transporter SLC26A6 and basolateral transporter SLC26A1 are each expressed in the epithelial tissues participating in oxalate homeostasis: intestine, liver and kidney. Moreover, the applicants have recently identified SLC26A6-mediated oxalate transport in macrophages. The overall goal of this project is to unravel the tissue-specific roles of SLC26A6 and SLC26A1 in oxalate homeostasis and kidney disease. During the next project period, the following specific aims will be pursued: 1. Determine tissue-specific roles of SLC26A6 and SLC26A1 in oxalate homeostasis. Generate mouse lines with tissue-specific disruption of the genes encoding SLC26A6 and SLC26A1 in intestine, liver and kidney, and characterize the tissue-specific roles of these transporters in defending against hyperoxalemia and hyperoxaluria resulting from ingested or endogenously produced oxalate loads. 2. Determine tissue-specific roles of SLC26A6 and SLC26A1 in defending against hyperoxalemia in CKD. Characterize tissue-specific roles of SLC26A6 and SLC26A1 in defending against hyperoxalemia in a model of CKD induced with aristolochic acid, and evaluate whether exaggerated hyperoxalemia resulting from tissue-specific deletion of SLC26A6 or SLC26A1 leads to accelerated progression of CKD. 3. Determine tissue-specific roles of SLC26A6 and SLC26A1 in the pathogenesis of oxalate-induced nephropathy. Characterize the role of SLC26A6 in mediating oxalate transport in inflammatory cells, assess the impact of deleting SLC26A6 specifically in inflammatory cells on oxalate-induced nephropathy, and assess the impact of kidney-specific deletion of SLC26A6 and SLC26A1 on oxalate nephropathy. The proposed studies will provide important new insights into the roles of oxalate transporters in governing urinary oxalate excretion in response to oxalate loading, in defending against hyperoxalemia and progressive loss of GFR in CKD, and in modifying oxalate-induced nephropathy.
Patients with high amounts of oxalate in the urine are at increased risk for calcium oxalate kidney stones and for calcium oxalate crystal deposits in the kidneys. By enhancing understanding of the molecular mechanisms affecting urinary oxalate excretion, the proposed studies will provide new insight into inherited and acquired causes of oxalate kidney stones and oxalate-induced kidney damage.
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