PDZ interactions and proximal tubular phosphate reabsorption

Biber, Jürg; Gisler, Serge M.; Hernando, Nati; Wagner, Carsten A.; Murer, Heini

doi:10.1152/ajprenal.00244.2004

Cited by 33 publications

(23 citation statements)

References 41 publications

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“…48 Its role as a signal molecule may be through Pit1-induced activation of a membrane-associated signaling complex similar to that known to associate with the sodium-dependent transport protein of the proximal tubule and osteoclasts, NaPi2a. 49 Our data in vivo were directly related to our in vitro model. In agreement with previous studies, 27 the BMP-2/MSX2 program was induced in the aorta by high-fat feeding, analogous to our basal condition hVSMC cultures from atherosclerotic donors; however, CKD was the major stimulus to VC in our model, analogous to the effect of phosphorus in vitro.…”

Section: Discussionmentioning

confidence: 73%

The Mechanism of Phosphorus as a Cardiovascular Risk Factor in CKD

Mathew¹,

Tustison²,

Sugatani³

et al. 2008

Journal of the American Society of Nephrology

208

171

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Hyperphosphatemia and vascular calcification have emerged as cardiovascular risk factors among those with chronic kidney disease. This study examined the mechanism by which phosphorous stimulates vascular calcification, as well as how controlling hyperphosphatemia affects established calcification. In primary cultures of vascular smooth muscle cells derived from atherosclerotic human aortas, activation of osteoblastic events, including increased expression of bone morphogenetic protein 2 (BMP-2) and the transcription factor RUNX2, which normally play roles in skeletal morphogenesis, was observed. These changes, however, did not lead to matrix mineralization until the phosphorus concentration of the media was increased; phosphorus stimulated expression of osterix, a second critical osteoblast transcription factor. Knockdown of osterix with small interference RNA (siRNA) or antagonism of BMP-2 with noggin prevented matrix mineralization in vitro. Similarly, vascular BMP-2 and RUNX2 were upregulated in atherosclerotic mice, but significant mineralization occurred only after the induction of renal dysfunction, which led to hyperphosphatemia and increased aortic expression of osterix. Administration of oral phosphate binders or intraperitoneal BMP-7 decreased expression of osterix and aortic mineralization. It is concluded that, in chronic kidney disease, hyperphosphatemia stimulates an osteoblastic transcriptional program in the vasculature, which is mediated by osterix activation in cells of the vascular tunica media and neointima. Chronic kidney disease (CKD) is a fatal illness, and cardiovascular complications are the major causes of morbidity and mortality. 1,2 The causes of the excess cardiovascular mortality associated with CKD are unknown, because the role of the standard risk factors associated with cardiovascular mortality do not account for the increased risk in CKD. 2 There is strong epidemiologic evidence that serum phosphorus is an independent risk factor for cardiovascular events and mortality in CKD. 3,4 The serum phosphorus has been linked to another cardiovascular risk factor, vascular calcification (VC), 3,5,6 an important cause of vascular stiffness in CKD leading to increased pulse wave velocity, increased cardiac work, left ventricular hypertrophy, and decreased coronary artery blood flow. 6 -8 Phosphorus has been further implicated as a cause of VC through studies in vitro that have demonstrated that it induces phenotypic changes in vascular smooth muscle cells (VSMC) by increasing gene transcription of proteins involved in osteoblast function-bone formation 9 and stimulating matrix mineralization. 10 -12 In the uremic calcifying environment, expression of the contractile proteins of VSMC, such as ␣-smooth muscle actin, SM22,

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Section: Discussionmentioning

confidence: 73%

The Mechanism of Phosphorus as a Cardiovascular Risk Factor in CKD

Mathew¹,

Tustison²,

Sugatani³

et al. 2008

Journal of the American Society of Nephrology

208

171

View full text Add to dashboard Cite

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“…The apical surface of renal proximal tubule cells is covered with densely packed microvilli which greatly increase the resorptive surface area. Each brush border microvillus is a specialized structure containing a central actin core, scaffolding or PDZ proteins thought to link membrane proteins to the actin cytoskeleton and myosin motors including myosin VI (5,7,21,22,31,39,40). The way in which these microvillar components interact to move NaPi2a out of the brush border microvillus in response to PTH remains unknown.…”

mentioning

confidence: 99%

PTH-induced internalization of apical membrane NaPi2a: role of actin and myosin VI

Blaine

Okamura

Giral

et al. 2009

American Journal of Physiology-Cell Physiology

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“…After expression cloning of NaPiIIa (24), the transporter responsible for most renal P i reabsorption, a complex network of interacting proteins that modulate the activity of this transporter has been described (for reviews, see Refs. 4,5,15,35).…”

mentioning

confidence: 99%

Interaction of MAP17 with NHERF3/4 induces translocation of the renal Na/Pi IIa transporter to thetrans-Golgi

Lanaspa¹,

Giral²,

Breusegem³

et al. 2007

American Journal of Physiology-Renal Physiology

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.-The function of the NaPiIIa renal sodium-phosphate transporter is regulated through a complex network of interacting proteins. Several PDZ domain-containing proteins interact with its COOH terminus while the small membrane protein MAP17 interacts with its NH 2 end. To elucidate the function of MAP17, we identified its interacting proteins using both bacterial and mammalian two-hybrid systems. Several PDZ domain-containing proteins, including the four NHERF proteins, as well as NaPiIIa and NHE3, were found to bind to MAP17. The interactions of MAP17 with the NHERF proteins and with NaPiIIa were further analyzed in opossum kidney (OK) cells. Expression of MAP17 alone had no effect on the NaPiIIa apical membrane distribution, but coexpression of MAP17 and NHERF3 or NHERF4 induced internalization of NaPiIIa, MAP17, and the PDZ protein to the trans-Golgi network (TGN). This effect was not observed when MAP17 was cotransfected with NHERF1/2 proteins. Inhibition of protein kinase C (PKC) prevented expression of the three proteins in the TGN. Activation of PKC in OK cells transfected only with MAP17 induced complete degradation of MAP17 and NaPiIIa. When lysosomal degradation was prevented, both proteins accumulated in the TGN. When the dopamine D1-like receptor was activated with fenoldopam, both NaPiIIa and MAP17 also accumulated in the TGN. Finally, cotransfection of MAP17 and NHERF3 prevented the adaptive upregulation of phosphate transport activity in OK cells in response to low extracellular phosphate. Therefore, the interaction between MAP17, NHERF3/4, and NaPiIIa in the TGN could be an important intermediate or alternate path in the internalization of NaPiIIa. phosphate transport; PDZ; PDZK1; protein interaction; opossum kidney cells RENAL REABSORPTION OF INORGANIC phosphate (P i ) and its regulation involve molecular mechanisms more complicated than initially thought. After expression cloning of NaPiIIa (24), the transporter responsible for most renal P i reabsorption, a complex network of interacting proteins that modulate the activity of this transporter has been described (for reviews, see Refs. 4,5,15,35).Most of the proteins that interact with this transporter contain one or more PDZ domains (acronym of the postsynaptic density protein PSD-95, the Drosophila junctional protein Disc-large, and the tight junction protein ZO1). These domains consist of 80 -90 amino acids that very often (but not always) scaffold specific proteins into supramolecular complexes (17). Several PDZ domain-containing proteins interact with the COOH end of NaPiIIa (12) DD96/SPAP is a small membrane protein that interacts with the NH 2 terminus of the phosphate transporter (28). MAP17 was first identified by differential display because its RNA was overexpressed in several carcinomas (18). In addition, it was also isolated during the expression cloning of a renal Na/D-mannose cotransport in Xenopus laevis oocytes, and it was considered to be an activator of a mannose transporter endogenous to the oocyte (6). Yeast two-hybrid experi...

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PDZ interactions and proximal tubular phosphate reabsorption

Cited by 33 publications

References 41 publications

The Mechanism of Phosphorus as a Cardiovascular Risk Factor in CKD

The Mechanism of Phosphorus as a Cardiovascular Risk Factor in CKD

PTH-induced internalization of apical membrane NaPi2a: role of actin and myosin VI

Interaction of MAP17 with NHERF3/4 induces translocation of the renal Na/Pi IIa transporter to thetrans-Golgi

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