Low Phosphate Diet Research Articles

Increased renal dopamine and acute renal adaptation to a high-phosphate diet

The current experiments explore the role of dopamine in facilitating the acute increase in renal phosphate excretion in response to a high-phosphate diet. Compared with a low-phosphate (0.1%) diet for 24 h, mice fed a high-phosphate (1.2%) diet had significantly higher rates of phosphate excretion in the urine associated with a two- to threefold increase in the dopamine content of the kidney and in the urinary excretion of dopamine. Animals fed a high-phosphate diet had a significant increase in the abundance and activity of renal DOPA (l-dihydroxyphenylalanine) decarboxylase and significant reductions in renalase, monoamine oxidase A, and monoamine oxidase B. The activity of protein kinase A and protein kinase C, markers of activation of renal dopamine receptors, were significantly higher in animals fed a high-phosphate vs. a low-phosphate diet. Treatment of rats with carbidopa, an inhibitor of DOPA decarboxylase, impaired adaptation to a high-phosphate diet. These experiments indicate that the rapid adaptation to a high-phosphate diet involves alterations in key enzymes involved in dopamine synthesis and degradation, resulting in increased renal dopamine content and activation of the signaling cascade used by dopamine to inhibit the renal tubular reabsorption of phosphate.

Parathyroid hormone/parathyroid hormone-related protein receptor signaling is required for maintenance of the growth plate in postnatal life

Parathyroid hormone (PTH)-related protein (PTHrP), regulated by Indian hedgehog and acting through the PTH/PTHrP receptor (PPR), is crucial for normal cartilage development. These observations suggest a possible role of PPR signaling in the postnatal growth plate; however, the role of PPR signaling in postnatal chondrocytes is unknown. In this study, we have generated tamoxifen-inducible and cartilage-specific PPR KO mice to evaluate the physiological role of PPR signaling in postnatal chondrocytes. We found that inactivation of the PPR in chondrocytes postnatally leads to accelerated differentiation of chondrocytes, followed by disappearance of the growth plate. We also observed an increase of TUNEL-positive cells and activities of caspase-3 and caspase-9 in the growth plate, along with a decrease in phosphorylation of Bad at Ser155 in postnatal PPR KO mice. Administration of a low-phosphate diet, which prevents apoptosis of chondrocytes, prevented the disappearance of the growth plate. Taken together, these observations suggest that the major consequences of PPR activation are similar in both the fetal and postnatal growth plates. Moreover, chondrocyte apoptosis through the activation of a mitochondrial pathway may be involved in the process of premature disappearance of the growth plate by postnatal inactivation of the PPR in chondrocytes.

Shank2 redistributes with NaPilla during regulated endocytosis.

Serum phosphate levels are acutely impacted by the abundance of sodium-phosphate cotransporter IIa (NaPiIIa) in the apical membrane of renal proximal tubule cells. PSD-95/Disks Large/Zonula Occludens (PDZ) domain-containing proteins bind NaPiIIa and likely contribute to the delivery, retention, recovery, and trafficking of NaPiIIa. Shank2 is a distinctive PDZ domain protein that binds NaPiIIa. Its role in regulating NaPiIIa activity, distribution, and abundance is unknown. In the present in vivo study, rats were maintained on a low-phosphate diet, and then plasma phosphate levels were acutely elevated by high-phosphate feeding to induce the recovery, endocytosis, and degradation of NaPiIIa. Western blot analysis of renal cortical tissue from rats given high-phosphate feed showed NaPiIIa and Shank2 underwent degradation. Quantitative immunofluorescence analyses, including microvillar versus intracellular intensity ratios and intensity correlation quotients, showed that Shank2 redistributed with NaPiIIa during the time course of NaPiIIa endocytosis. Furthermore, NaPiIIa and Shank2 trafficked through distinct endosomal compartments (clathrin, early endosomes, lysosomes) with the same temporal pattern. These in vivo findings indicate that Shank2 is positioned to coordinate the regulated endocytic retrieval and downregulation of NaPiIIa in rat renal proximal tubule cells.

Acute parathyroid hormone differentially regulates renal brush border membrane phosphate cotransporters

Renal phosphate reabsorption across the brush border membrane (BBM) in the proximal tubule is mediated by at least three transporters, NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3), and Pit-2 (SLC20A2). Parathyroid hormone (PTH) is a potent phosphaturic factor exerting an acute and chronic reduction in proximal tubule phosphate reabsorption. PTH acutely induces NaPi-IIa internalization from the BBM and lysosomal degradation, but its effects on NaPi-IIc and Pit-2 are unknown. In rats adapted to low phosphate diet, acute (30 and 60 min) application of PTH decreased BBM phosphate transport rates both in the absence and the presence of phosphonoformic acid, an inhibitor of SLC34 but not SLC20 transporters. Immunohistochemistry showed NaPi-IIa expression in the S1 to the S3 segment of superficial and juxtamedullary nephrons; NaPi-IIc was only detectable in S1 segments and Pit-2 in S1 and weakly in S2 segments of superficial and juxtamedullary nephrons. PTH reduced NaPi-IIa staining in the BBM with increased intracellular and lysosomal appearance. NaPi-IIa internalization was most prominent in S1 segments of superficial nephrons. We did not detect changes in NaPi-IIc and Pit-2 staining over this time period. Blockade of lysosomal protein degradation with leupeptin revealed NaPi-IIa accumulation in lysosomes, but no lysosomal staining for NaPi-IIc or Pit-2 could be detected. Immunoblotting of BBM confirmed the reduction in NaPi-IIa abundance and the absence of any effect on NaPi-IIc expression. Pit-2 protein abundance was also significantly reduced by PTH. Thus, function and expression of BBM phosphate cotransporters are differentially regulated allowing for fine-tuning of renal phosphate reabsorption.

Abstract 3789: Elevated inorganic phosphate stimulates immediate early gene expression and requires FGF receptor signaling

Abstract Dietary inorganic phosphate represents a novel chemoprevention target. Recent results from two different mouse models of tumorigenesis; the two-stage skin carcinogenesis and KrasLA1 lung tumor models suggest that a high phosphate diet increases tumor/papilloma number by approximately 50% relative to a low phosphate diet. Additionally, a low phosphate diet resulted in delayed incidence and growth of papillomas. These results suggest that increased consumption of dietary inorganic phosphate may have long-term consequences on overall health and particularly to tumorigenesis and consequently reducing dietary phosphate intake may be a novel chemoprevention strategy. Our in vitro studies have revealed an active role of inorganic phosphate in altering cell function in various cell types and suggest that the amount of available inorganic phosphate may have significant cell autonomous consequences on cell behavior including activation of ras and ERK1/2 signaling, and increased expression of transformation and metastasis associated genes such as osteopontin (spp1). However, the mechanism by which cells sense and respond to changes in extracellular phosphate resulting in increased proliferation and transformation is not fully understood. We have performed an analysis of the temporal changes in gene expression in response to elevated phosphate. Results identified the strong stimulation of immediate early genes within 15 minutes of exposure to elevated phosphate. Reporter and DNA binding assays revealed the requirement of serum response and AP-1 transcriptional elements and taken together characterize phosphate as a novel mitogen. Furthermore, we have identified the requirement of FGF receptor signaling as one of the earliest events in the phosphate signaling cascade. This finding provides a novel link between growth factor signaling, nutrient sensing and cell growth and tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3789.

GOUT OR NOT IN URAEMIC PATIENT

Address for Correspondence Shih-Hua Lin Division of Nephrology Department of Internal Medicine, Tri-Service General Hospital No.325, Sec. 2, Chenggong Rd., Neihu District Taipei City 114, Taiwan Tel.: 886-2-87927213 Fax: 886-2-87927134 E-mail: 1521116@ndmctsgh.edu.tw A 56-year-old uraemic woman on continuous ambulatory peritoneal dialysis (CAPD) for three years manifested a painful and enlarging mass over the left big toe for 2 weeks. She had a 6-year history of gout before the initiation of CAPD. On physical examinations, a fi xed palpable hard tender mass approximately 3 cm x 2 cm was in her swollen 1 metatarsophalangeal (MTP) joint of the left big toe without overlying warmth and erythema (Figure 1). Pertinent studies showed leucocytes 12.8 x 10 9 / L, erythrocyte sedimentation rate 100 mm/h, C-reactive protein concentrations 20.76 mg/dl, phosphorus 8.1 mg/dl, calcium 9.7 mg/dl, intact PTH 759 pg/ml. Gouty arthritis were tentatively diagnosed. The X-ray of the left foot revealed periarticular soft-tissue calcifi cation over the left 1 MTP joint (Figure 2). Besides, there also were multiple hard mass lesions over both wrists, hip joints, left shoulder, right elbow and right knee, compatible with uraemic tumoral calcinosis (UTC). With non-steroidal anti-infl ammatory drug, low phosphate diet and haemodialysis, the size of mass lesion was gradually decreased and relief of pain was noted over the ensuing 6 months. Figure 1. A tophi-like mass lesion over the base of 1 MTP joint

Elevated Phosphate Activates N-ras and Promotes Cell Transformation and Skin Tumorigenesis

Recent results suggest a paradigm shift from viewing inorganic phosphate as a passive requirement for basic cell functions to an active regulator of cell behavior. We have previously shown that elevated concentrations of phosphate increased cell proliferation and expression of protumorigenic genes such as Fra-1 and osteopontin in a preosteoblast cell line. Therefore, we hypothesized that elevated phosphate concentrations would promote cell transformation in vitro and tumorigenesis in vivo. Supplementation of medium with phosphate increased anchorage-independent transformation and proliferation of BALB/c mouse JB6 epidermal cells, activation of N-ras, ERK1/2, and activator protein-1, and increased gene expression of Fra-1, COX-2, and osteopontin in a dose-dependent manner. These in vitro results led to the hypothesis that varying the levels of dietary inorganic phosphate would alter tumorigenesis in the mouse model of skin carcinogenesis. Female FVB/N mice were treated with 7,12-dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol-13-acetate and fed high- or low-phosphate diets (1.2% versus 0.2% of the diet) for 19 weeks. The high-phosphate diet increased skin papilloma number by approximately 50% without changing feed intake and body weights. High dietary phosphate increased serum concentrations of phosphate, parathyroid hormone, and osteopontin and decreased serum concentrations of calcium. Thus, we conclude that elevated phosphate promotes cell transformation and skin tumorigenesis partly by increasing the availability of phosphate for activation of N-ras and its downstream targets, which defines reducing dietary phosphate as a novel target for chemoprevention.

Effect of Low Phosphate Diet on the Structure of the Rat Parathyroid and Thyroid Glands

Effect of Low Phosphate Diet on the Structure of the Rat Parathyroid and Thyroid Glands

Intestinal Npt2b Plays a Major Role in Phosphate Absorption and Homeostasis

Intestinal phosphate absorption occurs through both a paracellular mechanism involving tight junctions and an active transcellular mechanism involving the type II sodium-dependent phosphate cotransporter NPT2b (SLC34a2). To define the contribution of NPT2b to total intestinal phosphate absorption, we generated an inducible conditional knockout mouse, Npt2b(-/-) (Npt2b(fl/fl):Cre(+/-)). Npt2b(-/-) animals had increased fecal phosphate excretion and hypophosphaturia, but serum phosphate remained unchanged. Decreased urinary phosphate excretion correlated with reduced serum levels of the phosphaturic hormone FGF23 and increased protein expression of the renal phosphate transporter Npt2a. These results demonstrate that the absence of Npt2b triggers compensatory renal mechanisms to maintain phosphate homeostasis. In animals fed a low phosphate diet followed by acute administration of a phosphate bolus, Npt2b(-/-) animals absorbed approximately 50% less phosphate than wild-type animals, confirming a major role of this transporter in phosphate regulation. In vitro analysis of active phosphate transport in ileum segments isolated from wild-type or Npt2b(-/-) mice demonstrated that Npt2b contributes to >90% of total active phosphate absorption. In summary, Npt2b is largely responsible for intestinal phosphate absorption and contributes to the maintenance of systemic phosphate homeostasis.

A Calcified Gluteal Mass: Figure 1.

A 39-year-old man receiving chronic hemodialysis treatment for 11 years complained of an increasing mass in his left gluteal region 18 months after parathyroidectomy. He had not been compliant in taking phosphate binders and a low-phosphate diet. Parathyroidectomy had been carried out with reimplantation of some tissue in the right forearm. In the following months, …

PHOSPHATE MANAGEMENT—A DIETITIAN'S PERSPECTIVE

Hyperphosphataemia is a complication of renal failure which can lead to vascular calcification and hyperparathyroidism. Many factors influence phosphate levels, e.g. adherence to a low phosphate diet, adequate dialysis, hyperparathyroidism and concordance with phosphate binders. This article looks at the issues to consider and provides a dietitian's perspective on phosphate management.

EARLY INITIATION OF PHOSPHATE LOWERING DIETARY THERAPY IN NON‐DIALYSIS CHRONIC KIDNEY DISEASE: A CRITICAL REVIEW

Dietary management of hyperphosphatemia and hyperparathyroidism have long been important elements in the clinical management of CKD stage 4 and 5 for the prevention of mineral bone disease. The rationale for phosphate lowering has been further justified, given the accumulating data to support the association of phosphate with vascular damage, in this population who are at high risk of cardiovascular (CV) death. Phosphate is a novel CV risk factor in both CKD and in the general population, and a growing body of literature suggests that high normal serum phosphate may be a risk factor for progression of CKD. Few studies have examined hard outcomes after phosphate lowering. Nonetheless, given the balance of data both in cell, animal and human studies, the use of phosphate lowering strategies at earlier stages of CKD, perhaps even prior to serum phosphate level rising, may well be justified. This review will discuss the complications associated with higher serum phosphate, the potential benefits of early phosphate intervention, practical considerations of low phosphate diets and novel strategies for evaluating these strategies in clinical practice.

Nonfamilial hyperphosphatemic tumoral calcinosis with ulnar neuropathy

We present a case of multiple large juxta-articular painless masses involving both the elbows and right hip in a 27-year old south Asian male who presented with ulnar neuropathy and constitutional symptoms. Radiology, blood investigations and biopsy confirmed it to be hyperphosphatemic tumoral calcinosis. Patient was also diagnosed with an extremely rare association, testicular microlithiasis. Complete surgical excision with low phosphate diet resulted in complete neurological recovery and no recurrence at 30 months. Tumoral calcinosis should be considered in the differential diagnosis of a case with multiple, symptomatic juxta-articular masses.

PHOS GRAPH a novel tool in hyperphosphataemia management in haemodialysis patients

Background: In patients with end stage renal disease, hyperphosphataemia is an almost universal complication. Prolonged hyperphosphataemia is associated with increased morbidity and mortality (Kidney Disease Outcomes Quality Initiative‐K/DOQI, 2004). Pharmacological interventions such as phosphate binders are important in the management of hyperphosphataemia, but these need to be complemented by education regarding binder compliance with phosphate containing foods and limiting excessive phosphate intake. A previous audit carried out in September 2006 of the ‘knowledge of haemodialysis patients on a low phosphate diet and binders’ clearly indicated that we need to improve patients’ knowledge to achieve better control of hyperphosphataemia. The purpose of the study was to assess the effectiveness of an innovative method of patient education (Phos Graph) on the management of serum phosphate in haemodialysis patients with persistent hyperphosphataemia.Methods: The renal dietitians and the renal multi disciplinary team devised a tool called the Phos Graph. The Phos Graph is a novel patient information tool, to inform patients of their phosphate levels relative to their peers on dialysis. The Graph shows the upper limit and lower limit of the normal range, the patient's value for the month as well as their value for the previous month and a rank in comparison to their dialysis peers. Thirty‐four (of 129 patients on haemodialysis) patients with phosphate levels >1.8 mM were identified at the beginning of the study. These patients received a copy of the Phos Graph, an individual dietary assessment and a review of their low phosphate diet by the renal specialist dietitians. This study was carried out for three consecutive months (April to June 2007). The mean serum phosphate levels at the start and finish of the study were compared using the paired student two tailed t‐test. Statistical significance was taken at the P‐value <0.05.Results: Table 1 shows the comparison of phosphate levels for patients who received both, the Phos Graph and dietary intervention and those who received only Phos Graph. Mean phosphate levels during the 3 month study period Phosphate (mM) Start of study End of study P value >1.8 (Phos Graph + dietary intervention) n = 34 2.42 2.16 <0.05 <1.8 (Phos Graph without dietary intervention) n = 95 1.29 1.43 <0.05 Discussion: The study showed that there was a statistically significant reduction in phosphate levels during July 2007 for the 34 patients identified with raised levels in April 2007. However, the mean phosphate level at the end of the study is still above the recommended national level.Conclusion: In this pilot study ‘Phos Graph’ has proved to be a good tool to assist patients in managing hyperphosphataemia. However, it is difficult to distinguish whether it was the Phos Graph or individualized dietary care or both that resulted in improvements in serum phosphate levels. Further work on a larger group is needed to clarify this issue.Acknowledgment: We would like to thank Matthew Jones (Renal systems manager) and also to all Renal staff for their valuable support.References Block et al. (2004) Mineral metabolism, morbidity and mortality in maintenance haemodialysis patients. J. Am. Soc. Nephrol.15, 2208–2218.Kidney Disease Outcomes Quality Initiative (KDOQI). (2002) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease, Guideline 3. Evaluation of Serum Phosphorus Levels.Renal Association. Renal Association Standards Committee. (2002) Treatment of adults and children with renal failure: standards and audit measures, 3rd edn. Royal College of Physicians, London.The UK Renal Registry. (2005) Chapter 10: Bone Biochemistry: Serum Phosphate, Calcium, Parathyroid Hormone, Albumin and Aluminium. 8th Annual Report.

Assessing Knowledge of Haemodialysis Patients on Low Phosphate Diet and Binders

Assessing Knowledge of Haemodialysis Patients on Low Phosphate Diet and Binders

The progression of coronary artery calcification in predialysis patients on calcium carbonate or sevelamer

Coronary artery calcification is more prevalent in dialysis patients than in patients without kidney disease and this is associated with high serum phosphorus. In this study, we evaluate the effect of calcium carbonate or sevelamer treatments on the progression of calcification in 90 predialysis patients. Inclusion criteria were stable serum calcium, phosphorus, parathyroid hormone, and a similar baseline total calcium score (TCS). These patients were not treated by phosphate binder, vitamin D, or statin. They were given low-phosphorus diets without or with daily calcium carbonate or sevelamer throughout the study that averaged 2 years. Baseline demographic or clinical characteristics along with biochemical parameters were not different among the three groups. The TCS significantly increased in patients on the low-phosphorus diet alone, to a lesser extent in calcium carbonate-treated patients, and not at all in sevelamer-treated patients. The progression of coronary calcification paralleled that of the calcium score. Our study shows that sevelamer treatment should not be restricted to dialysis patients; however, a larger study should be undertaken to confirm these results.

Multi-modality study of the compositional and mechanical implications of hypomineralization in a rabbit model of osteomalacia

Osteomalacia is characterized by hypomineralization of the bone associated with increased water content. In this work we evaluate the hypotheses that 1) 3D solid-state magnetic resonance imaging (MRI) of 31 P ( SSI- PH) and 1 H ( SSI- WATER) of cortical bone can quantify the key characteristics of osteomalacia induced by low-phosphate diet; and 2) return to normophosphatemic diet ( NO) results in recovery of these indices to normal levels. Twenty female five-week old rabbits were divided into four groups. Five animals were fed a normal diet for 8 weeks ( NOI); five a hypophosphatemic diet (0.09%) for the same period to induce osteomalacia ( HYI). To examine the effect of recovery from hypophosphatemia an additional five animals received a hypophosphatemic diet for 8 weeks, after which they were returned to a normal diet for 6 weeks ( HYII). Finally, five animals received a normal diet for the entire 14 weeks ( NOII). The NOI and HYI animals were sacrificed after 8 weeks, the NOII and HYII groups after 14 weeks. Cortical bone was extracted from the left and right tibiae of all the animals. Water content was measured by SSI-WATER and by a previously reported spectroscopic proton–deuteron nuclear magnetic resonance (NMR) exchange technique ( NMR- WATER), phosphorus content by SSI-PH. All MRI and NMR experiments were performed on a 9.4 T spectroscopy/micro-imaging system. Degree of mineralization of bone ( DMB) was measured by μ-CT and elastic modulus and ultimate strength by 3-point bending. The following parameters were lower in the hypophosphatemic group: phosphorus content measured by SSI-PH (9.5 ± 0.4 versus 11.1 ± 0.3 wt.%, p < 0.0001), ash content (63.9 ± 1.7 versus 65.4 ± 1.1 wt.%, p = 0.05), ultimate strength, (96.3 ± 16.0 versus 130.7 ± 6.4 N/mm 2, p = 0.001), and DMB (1115 ± 28 versus 1176 ± 24 mg/cm 3, p = 0.003); SSI-WATER: 16.1 ± 1.5 versus 14.4 ± 1.1 wt.%, p = 0.04; NMR-WATER: 19.0 ± 0.6 versus 17.4 ± 1.2 wt.%, p = 0.01. Return to a normophosphatemic diet reduced or eliminated these differences (SSI-PH: 9.5 ± 0.9 versus 10.6 ± 0.8 wt.%, p = 0.04; DMB: 1124 ± 31 versus 1137 ± 10 mg/cm 3, p = 0.2; US: 95.6 ± 18.6 versus 103.9 ± 7.5 N/mm 2, p = 0.2; SSI-WATER: 12.4 ± 0.6 versus 12.2 ± 0.3 wt.%, p = 0.3) indicating recovery of the mineral density close to normal levels. Phosphorus content measured by SSI-PH was significantly correlated with DMB measured by μ-CT ( r 2 = 0.47, p = 0.001) as well as with ultimate strength ( r 2 = 0.54, p = 0.0004). The results show that the methods presented have potential for in situ assessment of mineralization and water, both critical to the bone's mechanical behavior.

Low dietary inorganic phosphate affects the brain by controlling apoptosis, cell cycle and protein translation

Inorganic phosphate (P i) plays a key role in diverse physiologic functions. In a previous study, we showed that high dietary P i perturbs brain growth through Akt/ERK signaling in developing mice. However, no study has investigated the response of the brain to low dietary P i. In this study, we addressed this question by studying the effects of low dietary P i on the cerebrum of developing mice. Two-week-old weaned mice were fed with a low phosphate diet for 4 weeks. At the end of the study, their cerebrum was dissected and signals important for protein translation, apoptosis and cell cycle were examined. The low phosphate diet did not cause physiologically significant changes; it increased the protein expression of phosphatase and tensin homolog deleted on chromosome 10 but decreased Akt activity. In addition, expression of eukaryotic translation initiation factor binding protein coupled with increased complex formation of eukaryotic translation initiation factor 4E/eukaryotic translation initiation factor binding protein 1 was induced in the cerebrum by low phosphate, leading to reduced cap-dependent protein translation. Finally, low phosphate facilitated apoptosis and suppressed signals important for the cell cycle in the cerebrum of dual-luciferase reporter mice. In summary, our results showed that a low phosphate diet affects the brain by controlling protein translation, apoptosis and cell cycle in developing mice. Our results support the hypothesis that P i works as a stimulus capable of increasing or decreasing several pivotal genes for normal development and suggest that regulation of P i consumption is important in maintaining a healthy life.

Advantage of a low glycemic index and low phosphate diet on diabetic nephropathy and aging-related diseases

Diabetic nephropathy is the leading cause of end-stage renal disease (ESRD) in Japan and other Westernized countries. Over 50% of the ESRD patients die from cardiovascular events. Cardiovascular disease (CVD) in ESRD patients with diabetes mellitus (DM) are implicated in the endothelial dysfunction caused by hyperglycemia, hyperlipidemia, and hypertension, and in the vascular calcification of intimal and medial arterial blood vessels caused by hyperphosphatemia. Therefore, dietary control of hyperglycemia and hyperphosphatemia should play an important role in the management of ESRD patients with DM. Furthermore, recent findings suggest that high concentrations of serum phosphate, even if within the normal range, may be a risk factor for CVD and mortality. An in vivo study using klotho knockout mice and fibroblast growth factor 23 (FGF-23) knockout mice has revealed that correction of hyperphosphatemia and hypervitaminosis D could ameliorate the premature aging-like phenotype. A low glycemic index and low phosphate diet may provide an advantage in the prevention of aging-related diseases in healthy individuals as well as in those with chronic kidney disease.

Rat Organic Anion Transporter 3 and Organic Anion Transporting Polypeptide 1 Mediate Perfluorooctanoic Acid Transport

The mechanism by which perfluorooctanoic acid (PFOA) is transported in the kidney was studied in rats. We hypothesized that some transporters that are expressed in the basolateral and/or brush border membrane of proximal tubular cells mediate the transport of PFOA. Mannitol infusion, which caused an increase in the urine flow rate, significantly increased the renal clearance (CLR) of PFOA in both male and female rats. Feeding a low-phosphate diet that causes an increase in the expression of rat type II sodium-dependent phosphate transporter (Npt2) reduced the CLR in both male and female rats. These suggest that PFOA is reabsorbed in the proximal tubules, and that a phosphate transporter may be responsible for the renal transport of PFOA. The CLR of PFOA in Eisai hyperbilirubinemic rats that lack multidrug resistance-associated protein 2 (MRP2) was not different from that of the wild type, suggesting that MRP2 is not responsible for the renal transport of PFOA. Three candidate transporters, organic anion-transporting polypeptide 1 (oatp1), Npt2, and organic anion transporter 3 (OAT3) were studied to clarify whether these transporters facilitate [14C]PFOA transport in functional studies in Xenopus laevis oocytes. Both oatp1 and OAT3 facilitated [14C]PFOA transport while Npt2 did not. These results suggest that both oatp1 and OAT3 mediate, at least in part, the transport of PFOA in the proximal tubules of rat kidney.