Renal

I am interested in the molecular physiology of salt and solute transport, and have exploited genomic databases to identify novel members of four transporter gene families. My laboratory has thus cloned several new members of the cation-chloride cotransporter gene family (1), including the novel K-Cl cotransporters KCC3 and KCC4 (4, 6), human KCC2 (10), and SLC12A9, a new family member with a novel membrane topology. We have directly characterized the genomic structure of the human orthologs, and have demonstrated that “peripheral neuropathy with or without agenesis of the corpus callosum” is due to loss-of-function mutations in the SLC12A6 gene encoding KCC3 (2). We recently characterized five new members of the SLC26 gene family (7); these include SLC26A6, a multifunctional anion exchanger that is the primary candidate for both the apical chloride-formate/oxalate exchanger in the renal proximal tubule (12) and the CFTR-dependent chloride-bicarbonate exchanger in the pancreas (7), and SLC26A9, a lung-specific chloride-base exchanger. Apical chloride-formate/oxalate/base exchange mediated by SLC26A6 and basolateral K-Cl cotransport mediated by KCC3 and KCC4 appear to play crucial roles in trans-epithelial salt transport by the proximal tubule (8, 11). Basolateral and apical oxalate exchange in the proximal tubule, mediated by SLC26A1 and SLC26A6, respectively (12), may also play a significant role in renal oxalate secretion (7).

The transport function of cloned transporters is primarily studied by isotopic flux measurements, using heterologous expression in Xenopus laevis oocytes. In addition, the electrogenic properties of the SLC26 exchangers (7) and other transporters leave them amenable to electrophysiological analysis. Isoform-specific functional properties provide a starting point for structure-function analysis, using chimeric and mutant cDNAs. Immunolocalization of transporter transcripts and proteins has also provided important information on physiological roles in the kidney (5) and brain (3, 9), which have guided the physiological characterization of the relevant knockout mice (2)

Recent Publications:

1. Delpire E and Mount DB. Human and murine phenotypes associated with defects in cation-chloride cotransport. Annu Rev Physiol 64: 803-843, 2002.
   
   
2. Howard HC, Mount DB, et al. The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet 32: 384-392, 2002.
   
   
3. Karadsheh MF, Byun N, Mount DB, and Delpire E. Localization of the KCC4 K-Cl cotransporter in the nervous system. Neuroscience, 2003.
   
   
4. Mercado A, Song L, Vazquez N, Mount DB, and Gamba G. Functional Comparison of the K+-Cl- Cotransporters KCC1 and KCC4. J Biol Chem 275: 30326-30334, 2000..
   
   
5. Mount DB, et al. Isoforms of the apical Na-K-2Cl transporter in murine thick ascending limb. I: Molecular characterization and intra-renal localization. Am J Physiol 276: F347-F358, 1999.
   
   
6. Mount DB, et al. Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family. J Biol Chem 274: 16355-16362, 1999.
   
   
7. Mount DB and Romero MF. The SLC26 gene family of multifunctional anion exchangers. Pflugers Arch, 2003.
   
   
8. Mount DB, Song L, Mercado A, Gamba G, and Delpire E. Basolateral localization of renal tubular K-Cl cotransporters. J Am Soc Nephrol 11: 35A, 2000.