The present proposal is for continuation of a long-standing research program that had been directed at studying the ion exchangers mediating acid-base and NaCI transport in the proximal tubule. As part of this program, the applicants identified and characterized a novel anion exchanger (SLC26A6) that was named CFEX based on its ability to mediate Cl-formate exchange. They also found that a second related transporter, SLC26A7, is also expressed on the apical membrane of proximal tubule cells. Their recent studies using CFEX null mice have revealed that CFEX, by virtue of its activity as a Cl-oxalate exchanger, plays essential roles in proximal tubule NaCI absorption and intestinal oxalate secretion. They demonstrated that the latter process is critical to limiting net intestinal absorption of oxalate and preventing hyperoxaluria and calcium oxalate urolithiasis. Although the applicants plan to continue to examine the roles of CFEX and SLC26A7 in proximal tubule NaCI transport, a major new translational research effort will focus on the use of mouse models to elucidate the roles of CFEX and related transporters in the integrative physiology of oxalate homeostasis and the pathogenesis of hyperoxaluria and urolithiasis. Thus, the specific aims are to: 1) Evaluate the contribution of CFEX to mediating proximal tubule NaCI transport in vivo, and also assess the role of SLC26A7 in mediating components of proximal tubule Cl transport not attributable to CFEX;2) Evaluate the role of CFEX in mediating proximal tubule oxalate transport, and also assess the role of SLC26A7 in mediating components of proximal tubule oxalate transport not attributable to CFEX;3) Evaluate the role of CFEX in mediating intestinal oxalate transport, and also assess the role of other SLC26 transporters in mediating components of intestinal oxalate transport not attributable to CFEX;4) Evaluate the potential role of CFEX mutations in causing hyperoxaluria in patients with urolithiasis;and 5) Evaluate the roles of CFEX-associated proteins in regulating intestinal oxalate transport and oxalate homeostasis. By enhancing understanding of the molecular mechanisms affecting urinary oxalate excretion, the proposed studies may provide new insight into genetic causes of increased stone risk, and may identify novel therapeutic targets to reduce oxalate excretion and thereby decrease stone risk. The proposed studies are also relevant to clinical disorders of NaCI homeostasis such as hypertension and congestive heart failure.
| Knauf, Felix; Velazquez, Heino; Pfann, Victoria et al. (2018) Characterization of renal NaCl and oxalate transport in Slc26a6-/- mice. Am J Physiol Renal Physiol : |
| Ermer, Theresa; Kopp, Christoph; Asplin, John R et al. (2017) Impact of Regular or Extended Hemodialysis and Hemodialfiltration on Plasma Oxalate Concentrations in Patients With End-Stage Renal Disease. Kidney Int Rep 2:1050-1058 |
| Knauf, Felix; Thomson, Robert B; Heneghan, John F et al. (2017) Loss of Cystic Fibrosis Transmembrane Regulator Impairs Intestinal Oxalate Secretion. J Am Soc Nephrol 28:242-249 |
| Mulay, Shrikant R; Eberhard, Jonathan N; Pfann, Victoria et al. (2016) Oxalate-induced chronic kidney disease with its uremic and cardiovascular complications in C57BL/6 mice. Am J Physiol Renal Physiol 310:F785-F795 |
| Thomson, R Brent; Thomson, Claire L; Aronson, Peter S (2016) N-glycosylation critically regulates function of oxalate transporter SLC26A6. Am J Physiol Cell Physiol 311:C866-C873 |
| Ermer, Theresa; Eckardt, Kai-Uwe; Aronson, Peter S et al. (2016) Oxalate, inflammasome, and progression of kidney disease. Curr Opin Nephrol Hypertens 25:363-71 |
| Jalali, R; Zandieh-Doulabi, B; DenBesten, P K et al. (2015) Slc26a3/Dra and Slc26a6 in Murine Ameloblasts. J Dent Res 94:1732-9 |
| Knauf, Felix; Asplin, John R; Granja, Ignacio et al. (2013) NALP3-mediated inflammation is a principal cause of progressive renal failure in oxalate nephropathy. Kidney Int 84:895-901 |
| Jacques, Thibaut; Picard, Nicolas; Miller, R Lance et al. (2013) Overexpression of pendrin in intercalated cells produces chloride-sensitive hypertension. J Am Soc Nephrol 24:1104-13 |
| Ko, Narae; Knauf, Felix; Jiang, Zhirong et al. (2012) Sat1 is dispensable for active oxalate secretion in mouse duodenum. Am J Physiol Cell Physiol 303:C52-7 |
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