The regulation of the overall renal tubular Pi transport by dietary, hormonal, or metabolic factors occurs via the proximal tubular apical brush border membrane (BBM) sodium gradient-dependent Pi (NaPi) cotransport proteins. Apical entry of Pi is mediated by coordinated actions of NaPi-2a, NaPi-2c, and PiT-2. Chronic alterations in dietary Pi, PTH, FGF23, Klotho, and other metabolic and dietary factors change the abundance of these transporters in BBM. There are however several important differences between these NaPi cotransporters the most important being that a) the time scale kinetics of the regulation of the NaPi transporters by dietary Pi and PTH are quite different, and b) there is also increasing evidence for the differential regulation of the NaPi transporters. This proposal will test the HYPOTHESES that NaPi-2a, NaPi-2c and PiT-2 are localized in distinct brush border membrane microdomains or nanodomains, resulting in: 1) differential regulation of lateral diffusion and clustering of the NaPi transporters in the brush border membrane;2) differential interactions with PDZ and ERM domain containing proteins, including NHERF-1, PDZK-1, and ezrin;3) differential rates of recruitment to endocytic pathways and/or differential mechanisms of endocytosis and internalization from the brush border membrane.
AIM 1 will determine if NaPi-2a, NaPi-2c and PiT-2 are localized in distinct BBM microdomains or nanodomains resulting in differential regulation of lateral diffusion and clustering of the NaPi transporters in the BBM in response to alterations in PTH, Pi, membrane lipid composition and actin dynamics.
AIM 2 will determine if NaPi-2a, NaPi-2c and PiT-2 have differential interactions with PDZ -ERM domain proteins, including NHERF-1, PDZK-1, and ezrin, which result in the differential internalization rate of the NaPi transporters in response to alterations in PTH, Pi and lipids.
AIM 3 will determine if NaPi-2a, NaPi-2c and PiT-2 have differential rates of recruitment to endocytic pathways and/or differential mechanisms of endocytosis and internalization from the brush border membrane in response to PTH, Pi and lipids.
Disorders of Pi concentration are common clinical problems in aging, diabetes, cancer, chronic kidney disease, and AIDS by altering renal Pi absorption. Hyperphosphatemia results in vascular calcification and cardiac disease. Hypophosphatemia results in impaired energy production and bone mineralization. Genetic mutations of Pi transporters also cause bone disease, kidney stone formation, and kidney calcification.
|Lanaspa, Miguel A; Caldas, Yupanqui A; Breusegem, Sophia Y et al. (2013) Inorganic phosphate modulates the expression of the NaPi-2a transporter in the trans-Golgi network and the interaction with PIST in the proximal tubule. Biomed Res Int 2013:513932|
|Hegan, Peter S; Giral, Hector; Levi, Moshe et al. (2012) Myosin VI is required for maintenance of brush border structure, composition, and membrane trafficking functions in the intestinal epithelial cell. Cytoskeleton (Hoboken) 69:235-51|
|Lanzano, Luca; Gratton, Enrico (2012) Measurement of distance with the nanoscale precise imaging by rapid beam oscillation method. Microsc Res Tech 75:1253-64|
|Lim, Ryan S; Suhalim, Jeffrey L; Miyazaki-Anzai, Shinobu et al. (2011) Identification of cholesterol crystals in plaques of atherosclerotic mice using hyperspectral CARS imaging. J Lipid Res 52:2177-86|
|Caldas, Yupanqui A; Giral, Hector; Cortazar, Michael A et al. (2011) Liver X receptor-activating ligands modulate renal and intestinal sodium-phosphate transporters. Kidney Int 80:535-44|
|Giral, Hector; Lanzano, Luca; Caldas, Yupanqui et al. (2011) Role of PDZK1 protein in apical membrane expression of renal sodium-coupled phosphate transporters. J Biol Chem 286:15032-42|
|Ahmad, Aamir; Khundmiri, Syed J; Pribble, Francesca et al. (2011) Role of vacuolar ATPase in the trafficking of renal type IIa sodium-phosphate cotransporter. Cell Physiol Biochem 27:703-14|
|Blaine, Judith; Lanzano, Luca; Giral, Hector et al. (2011) Dynamic imaging of the sodium phosphate cotransporters. Adv Chronic Kidney Dis 18:145-50|
|Lanzano, Luca; Digman, Michelle A; Fwu, Peter et al. (2011) Nanometer-scale imaging by the modulation tracking method. J Biophotonics 4:415-24|
|Lanzano, Luca; Lei, Tim; Okamura, Kayo et al. (2011) Differential modulation of the molecular dynamics of the type IIa and IIc sodium phosphate cotransporters by parathyroid hormone. Am J Physiol Cell Physiol 301:C850-61|
Showing the most recent 10 out of 28 publications