Renal Tubular Transport Research Articles

FGF23 regulation of renal tubular solute transport.

Fibroblast growth factor-23 (FGF23) is a bone-derived hormone known to suppress phosphate reabsorption in the kidney. The purpose of this review was to highlight the recent advances in the area of FGF23-regulated solute transport in the kidney. Recent evidence suggests that FGF23 suppresses phosphate reabsorption in renal proximal tubular epithelium by a Klotho-dependent, FGF receptor (FGFR)-1 and FGFR4-mediated signaling mechanism that may also involve Janus kinase 3. Moreover, it was recently established that FGF23 signaling in the distal renal tubule targets with-no-lysine kinase-4 (WNK4), a key molecule in the regulation of solute transport in the distal nephron. By targeting WNK4, FGF23 has been shown to increase the membrane abundance of the epithelial calcium channel TRPV5 and of the sodium-chloride cotransporter NCC, resulting in augmented renal calcium and sodium reabsorption. Significant progress has been made in the further characterization of the signaling pathways involved in the FGF23-induced inhibition of phosphate transport in proximal tubular epithelium, and major new functions of FGF23 in solute transport have been discovered in distal renal tubules. The calcium- and sodium-conserving functions of FGF23 may have major implications for the pathophysiology of cardiovascular diseases. VIDEO ABSTRACT.

Editorial: The emerging discipline of quantitative systems pharmacology.

Editorial: The emerging discipline of quantitative systems pharmacology.

Maintaining Balance Under Pressure: Integrated Regulation of Renal Transporters During Hypertension.

Hypertension is the leading cause of stroke and cardiovascular diseases and a leading risk factor for global disease burden, affecting 30% of the adult population in Western cultures.1 Blood pressure (BP) can be elevated by vasoconstriction and by increasing the circulating volume. Evidence from studies of mutations in renal Na+ transporters, renal transplantation, and diuretic action supports Guyton’s hypothesis that long-term regulation of effective circulating volume and BP depends on fractional renal Na+ reabsorption.2–4 Ultimately, excess Na+ reabsorption (Figure, red arrows) raises effective circulating volume and BP which provoke counteracting natriuretic responses to match Na+ output to Na+ intake at the expense of elevated BP (Figure, blue arrow).2 We and others have determined that pressure natriuresis responses involve Na+ transporter inhibition at multiple levels of regulation.5–13 According to Guyton, kidneys possess the capacity to excrete enough Na+ and volume to normalize BP in the face of expanded effective circulating volume.2 Thus, hypertension can be characterized as a failure of compensatory renal pressure natriuresis. Indeed, there is strong evidence that the pressure natriuresis response is impaired during experimental hypertension by inflammation, immune cell infiltration, and intrarenal angiotensin II (AngII) production, secondary to initiating stimuli such as AngII infusion, reduced NO production, high-salt diet, or elevated renal sympathetic nerve activity.14–17 This brief review focuses on the natriuretic effectors and addresses (1) the renal tubular locations and transporters that participate in pressure natriuresis and (2) the mechanisms that blunt the response in experimental models of hypertension. Figure. Renal transporter profile reveals region specific transporter regulation during experimental hypertension. A , Anatomic arrangement of renal cortex and renal medulla in a kidney cross-section …

Editorial introductions

Editorial introductions

Renal clearance of uric acid is linked to insulin resistance and lower excretion of sodium in gout patients.

Inefficient renal excretion of uric acid is the main pathophysiological mechanism for hyperuricemia in gout patients. Polymorphisms of renal tubular transporters linked with sodium and monosaccharide transport have yet to be demonstrated. We intended to evaluate the impact of insulin resistance, evaluated with the homeostasis model assessment (HOMA), through a transversal study of non-diabetic patients with gout, with normal renal function, not treated with any medication but colchicine as prophylaxis. One hundred and thirty-three patients were evaluated. Clearance of uric acid was inversely correlated with insulin resistance and directly correlated with fractional excretion of sodium. In multivariate analysis, hypertension and hyperlipidemia, in addition to insulin resistance and fractional excretion of sodium, were associated with renal clearance of uric acid. HOMA cutoff for efficient versus inefficient renal handling of uric acid was 2.72, close to that observed in studies of reference population. The impact of insulin resistance and renal handling of sodium on renal clearance of uric acid may help to explain why hyperuricemia is more commonly associated with diabetes and hypertension.

The urinary levels of prostanoid metabolites predict acute kidney injury in heterogeneous adult Japanese ICU patients: a prospective observational study.

Acute kidney injury (AKI) is frequently observed in critically ill patients in the intensive care unit (ICU) and is associated with increased mortality. Prostanoids regulate numerous biological functions, including hemodynamics and renal tubular transport. We herein investigated the ability of urinary prostanoid metabolites to predict the onset of AKI in critically ill adult patients. The current study was conducted as a prospective observational study. Urine of patients admitted to the ICU at Okayama University Hospital was collected and the urinary levels of prostaglandin E2 (PGE2), PGI2 metabolite (2,3-dinor-6-OXO-PGF1α), thromboxane A2 (TXA2) metabolite (11-dehydro-TXB2) were determined. Of the 93 patients, 24 developed AKI (AKIN criteria). Surgical intervention (93, 75 %) was the leading cause of ICU admission. Overall, the ratio of the level of serum Cr on Day 1 after ICU admission to that observed at baseline positively correlated with the urinary 2,3-dinor-6-OXO-PGF1α/Cr (r = 0.57, p < 0.0001) and 11-dehydro-TXB2/Cr (r = 0.47, p < 0.0001) ratios. In 16 cases of de novo AKI, the urinary 2,3-dinor-6-OXO-PGF1α/Cr and 11-dehydro-TXB2/Cr values were significantly elevated compared with that observed in the non-AKI group, whereas the urinary PGE2/Cr values were not. The urinary 2,3-dinor-6-OXO-PGF1α/Cr ratio exhibited the best diagnostic and predictive performance among the prostanoid metabolites according to the receiver operating characteristic (ROC) analysis [ROC-area under the curve (AUC): 0.75]. Taken together, these results demonstrate that the urinary 2,3-dinor-6-OXO-PGF1α/Cr and 11-dehydro-TXB2/Cr ratios are associated with the subsequent onset of AKI and poor outcomes in adult heterogeneous ICU patients.

Protease Inhibitors and Renal Function in Patients with HIV Infection: a Systematic Review.

IntroductionDespite antiretroviral (ARV) therapy reducing renal disease in human immunodeficiency virus overall, there is concern that certain ARVs, particularly tenofovir disoproxil fumarate (TDF) with or without a boosted protease inhibitor (PI), may reduce renal function over time. It is not known whether effects seen with PI-based regimens are independent, result from interactions with TDF coadministration, or are artefactual owing to inhibition of renal tubular creatinine transport by ritonavir or cobicistat pharmacoenhancement. The aim of this review was to conduct a systematic review of studies, weighted toward high-quality evidence, examining changes in renal function over time with PI-based regimens.MethodsPubMed, Embase, and Medline databases and conference abstracts were searched using pre-defined terms for English language articles, published up to and including August 12, 2013, describing changes in renal function over time with PI-based regimens. All available randomized controlled trials (RCTs) were selected; however, to reduce bias, only observational studies recruiting from more than one center and analyzing data from more than 1,000 patients were included. Evidence was qualitatively evaluated according to levels established by the Oxford Centre for Evidence-Based Medicine (OCEBM).ResultsA total of 2,322 articles were retrieved by the initial search. Of these, 37 were selected for full review, comprising 24 RCTs (OCEBM Level 1 evidence: 4 reports of fully double-blinded or blinded with respect to the PI component). The remaining 20 RCTs and 13 observational studies qualified as OCEBM Level 2 evidence. Level 1 evidence showed initial but non-progressive increases in serum creatinine and corresponding decreases in estimated glomerular filtration rate (eGFR), suggesting an effect on renal tubular transport of creatinine. Level 2 evidence suggested that atazanavir and lopinavir especially in combination with TDF were associated with non-progressive reductions in eGFR over time, with a decreased risk for the development of chronic kidney disease (CKD) on cessation and without the development of advanced CKD or end-stage renal disease (ESRD); whether these reductions were independent or associated with interactions with coadministered TDF could not be established with certainty. Data on darunavir were insufficient to draw any conclusions. The principal limitation of the reviewed studies was the lack of standardization of creatinine measurements in virtually all studies and the lack of corroborative data on changes in proteinuria or other indices of renal function.DiscussionIn this review, there was little evidence for progressive changes in eGFR, or the development of advanced CKD, or ESRD with lopinavir or atazanavir. Further long-term studies, employing a wide range of validated renal function assessments, are required to fully evaluate potential association of PIs with CKD.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-014-0056-4) contains supplementary material, which is available to authorized users.

Roles of Akt and SGK1 in the Regulation of Renal Tubular Transport.

A serine/threonine kinase Akt is a key mediator in various signaling pathways including regulation of renal tubular transport. In proximal tubules, Akt mediates insulin signaling via insulin receptor substrate 2 (IRS2) and stimulates sodium-bicarbonate cotransporter (NBCe1), resulting in increased sodium reabsorption. In insulin resistance, the IRS2 in kidney cortex is exceptionally preserved and may mediate the stimulatory effect of insulin on NBCe1 to cause hypertension in diabetes via sodium retention. Likewise, in distal convoluted tubules and cortical collecting ducts, insulin-induced Akt phosphorylation mediates several hormonal signals to enhance sodium-chloride cotransporter (NCC) and epithelial sodium channel (ENaC) activities, resulting in increased sodium reabsorption. Serum- and glucocorticoid-inducible kinase 1 (SGK1) mediates aldosterone signaling. Insulin can stimulate SGK1 to exert various effects on renal transporters. In renal cortical collecting ducts, SGK1 regulates the expression level of ENaC through inhibition of its degradation. In addition, SGK1 and Akt cooperatively regulate potassium secretion by renal outer medullary potassium channel (ROMK). Moreover, sodium-proton exchanger 3 (NHE3) in proximal tubules is possibly activated by SGK1. This review focuses on recent advances in understanding of the roles of Akt and SGK1 in the regulation of renal tubular transport.

P2X receptors trigger intracellular alkalization in isolated perfused mouse medullary thick ascending limb.

AimsExtracellular ATP is an important regulator of renal tubular transport. Recently, we found that basolateral ATP markedly inhibits Na+ and Cl− absorption in mouse medullary thick ascending limb (mTAL) via a P2X receptor. The underlying mechanism that mediates this ATP-dependent transport inhibition in mTAL is, however, unclear. The renal outer medullary K+ channel (ROMK) is sensitive to intracellular pH where a reduction leads to closing of ROMK. We speculated that P2X receptor stimulation in the TAL could lead to changes in pHi, leading to a reduction in NaCl transport.MethodsTo test this hypothesis, we measured pHi in single perfused mouse mTALs using the fluorescent ratiometric dye 2′,7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein acetoxymethylester.ResultsInterestingly, basolateral ATP (100 μm) caused a prominent, reversible intracellular alkalization of mTAL, with an average pHi increase of 0.14 ± 0.02 (n = 14). This was completely abolished by the P2X receptor antagonist periodate-oxidized ATP (50 μm). The P2X receptor-mediated intracellular alkalization required the activity of the apical Na+/H+ exchanger (NHE3). Typically, Gq-coupled receptors cause a significant acidification of tubular epithelial cells, which was confirmed in this study, by P2Y2 and Ca2+ sensing receptor stimulation.ConclusionThis study reports that stimulation of basolateral P2X receptors causes a substantial intracellular alkalization in the isolated perfused mouse mTAL. This intracellular alkalization is mediated through an increased apical NHE3 activity, similar to what we previously observed when tubular transport is inhibited with furosemide. This increased NHE3 activity causes H+ secretion in the mTAL and provides further support that the TAL is a site of urinary acidification.

Adverse events: ART and the kidney: alterations in renal function and renal toxicity.

Renal dysfunction is common in HIV-positive patients who receive antiretroviral therapy (ART). Several antiretrovirals have been associated with kidney disease progression, inhibition of renal tubular transporters that mediate creatinine secretion or impaired reabsorption of phosphate and low-molecular weight proteins. These aberrations of renal function are typically non-treatment limiting and of unclear clinical significance. By contrast, severe renal toxicity is infrequent in well-managed patents. Tenofovir-DF and atazanavir may cause acute tubular injury, tubule-interstitial nephritis or nephrolithiasis. Discontinuation of the offending drug is required to mitigate the adverse effects on kidney or bone. This presentation will discuss ART-associated changes in renal function and treatment-limiting renal toxicity in terms of incidence, risk factors, putative mechanism and provide recommendations for clinical practice.

SY10-3 - Factors Influencing the Onset of Chemotherapy-Induced Adverse Events Including Drug-Drug Interaction

It is important for cancer chemotherapy to maintain effective response with minimizing undesired drug effects. Individual differences of pharmacokinetics (PK) and pharmacodynamics (PD) of anticancer drugs contribute a great deal to the development of adverse events. With regard to PK change, decrease in renal clearance due to renal failure or drug-drug interaction is one of the most serious problem for drugs mainly excreted by the kidney. Folic acid analogs are typical drugs excreted by the kidney. Recently, we indicated that pemetrexed, one of the folic acid analogs, is a superior substrate to methotrexate for hOAT3 (SLC22A8), and nonsteroidal anti-inflammatory drugs (NSAIDs) could cause drug-drug interaction via renal tubular transport by OAT3 when attaining their high plasma concentrations 1). Incidentally, almost all of small molecule anticancer drugs, which targets intracellular signaling pathway, are metabolized by hepatic cytochrome P450 (CYP) 3A. Strong inhibitors of CYP3A are sometimes used together with the small molecular drugs and increase their plasma concentration, which results in increased risk of toxicities. We previously showed that strong CYP3A inhibitor, itraconazole, appeared to exacerbate peripheral neuropathy and thrombocytopenia caused by bortezomib, a proteasome inhibitor 2). Furthermore, we found out that carboplatin-induced severe allergy after multiple dose of the drugs accompanied the change in immunological reaction, which was obviously confirmed by basophil activation 3), whereas a toxicological study focused on PD change during chemotherapy is still limited.In this symposium, we will summarize our recent findings about the risk of chemotherapy-induced toxicities, which involves the changes in PK/PD of anticancer drugs in clinical settings.1) Kurata T et al., Drug Metab Pharmacokinet (2014)2) Iwamoto T et al., Pharmacotherapy (2010)3) Iwamoto T et al., Biol Pharm Bull (2012)

The calcium-activated chloride channel Anoctamin 1 contributes to the regulation of renal function

The role of calcium-activated chloride channels for renal function is unknown. By immunohistochemistry we demonstrate dominant expression of the recently identified calcium-activated chloride channels, Anoctamin 1 (Ano1, TMEM16A) in human and mouse proximal tubular epithelial (PTE) cells, with some expression in podocytes and other tubular segments. Ano1-null mice had proteinuria and numerous large reabsorption vesicles in PTE cells. Selective knockout of Ano1 in podocytes (Ano1-/-/Nphs2-Cre) did not impair renal function, whereas tubular knockout in Ano1-/-/Ksp-Cre mice increased urine protein excretion and decreased urine electrolyte concentrations. Purinergic stimulation activated calcium-dependent chloride currents in isolated proximal tubule epithelial cells from wild-type but not from Ano1-/-/Ksp-Cre mice. Ano1 currents were activated by acidic pH, suggesting parallel stimulation of Ano1 chloride secretion with activation of the proton-ATPase. Lack of calcium-dependent chloride secretion in cells from Ano1-/-/Ksp-Cre mice was paralleled by attenuated proton secretion and reduced endosomal acidification, which compromised proximal tubular albumin uptake. Tubular knockout of Ano1 enhanced serum renin and aldosterone concentrations, probably leading to enhanced compensatory distal tubular reabsorption, thus maintaining normal blood pressure levels. Thus, Ano1 has a role in proximal tubular proton secretion and protein reabsorption. The results correspond to regulation of the proton-ATPase by the Ano1-homolog Ist2 in yeast.

Increased renal oxygen consumption leads to hypoxia in sepsis‐associated acute kidney injury (890.9)

We have shown in subtotal nephrectomy (STN), a model of chronic kidney disease, there is increased oxygen consumption (QO2) factored for tubular Na reabsorption (TNa) leading to hypoxia. To demonstrate the universality of hypoxia in the pathogenesis of kidney disease, we have now examined renal oxygenation (oxygen delivery and consumption), mitochondrial function and tubular transport in acute kidney injury (AKI) due to sepsis in a rat model of cecal ligation and puncture (CLP). Data presented as mean±sem.At 6 and 24 hours, GFR was significantly lower in CLP (2.5±0.4 vs. 3.6±0.2 ml/min and 1.2±0.3 vs. 3.3±0.2 ml/min, p&lt;0.001). While RBF and O2 delivery was largely unchanged, renal O2 extraction and QO2 factored for GFR was higher compared to shams, (0.023±0.002 vs. 0.01±0.001 vol%ml/min and 0.11±0.01 vs. 0.05±0.01 ml/min,p&lt;0.04). HIF‐1a expression was upregulated in the CLP kidneys at both 6 and 24 hours. In CLP, we found elevated rates of mitochondrial QO2 (199.9 ± 31.6 pMol/min vs. 163.2 ± 28.81 pMol/min, p&lt;0.05), but significantly lower ATP generation with reduced expression of complex Va and complex III (p&lt;0.05 for both). Proteins regulating mitochondrial morphology were also altered with increased expression of fission protein DRP1 (P&lt;.0004) and decreased expression of PGC‐1alpha, a factor in mitochondrial biogenesis (2.2‐fold lower) in CLP. HIF‐1α activation by DMOG improved GFR at both time points.We demonstrate increased renal QO2 despite lower GFR leading to hypoxia and dissociation between excess QO2 and ATP generation in CLP mitochondria. We are investigating alterations in mitochondrial dynamics which could explain mitochondrial dysfunction and tubular injury, and the role of HIF‐1α pathway in this. In conclusion, our data in both acute and chronic kidney injury model demonstrates early hypoxia due to increased oxygen consumption leading to oxygen demand‐supply mismatch and strongly supports the role of hypoxia as a unifying mechanism for kidney disease.Grant Funding Source: NIH

Assessment of tubular reabsorption of phosphate as a surrogate marker for phosphate regulation in chronic kidney disease

Fibroblast growth factor 23 (FGF23) and soluble α-Klotho are emerging potential biomarkers of phosphorus and vitamin D metabolism which change in concentration in early chronic kidney disease (CKD) in order to maintain normal phosphorus levels. Tubular reabsorption of phosphate (TRP) has been commonly used to assess renal tubular phosphate transport. The aim of this study was to evaluate the usefulness of TRP as a surrogate marker of parameters of CKD-mineral bone disease (CKD-MBD) in CKD. A cross-sectional study was performed in 93 stable patients with predialysis CKD stage 1-5. In all patients, TRP, estimated glomerular filtration rate (eGFR), calcium, phosphate, intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, serum FGF23 and urine soluble α-Klotho levels were measured. As renal function declined, TRP significantly decreased (P < 0.001; r = 0.763) and both iPTH and serum FGF23 increased (P < 0.001; r = -0.598, P < 0.001; r = -0.453, respectively). The prevalence of hyperphosphatemia, secondary hyperparathyroidism, FGF23 excess and abnormal TRP increased progressively with declining eGFR. Although TRP level changed later than FGF23, abnormal levels of both TRP and FGF23 were observed earlier than changes in iPTH and serum phosphate. Decreased TRP was found to be independently associated with decreased eGFR and increased iPTH but was not associated with urine soluble α-Klotho or serum FGF23 level in multiple linear regression analysis. TRP is a simple, useful and cost-saving surrogate marker of the assessment of altered mineral metabolism in CKD patients and can be used as an alternative to serum FGF23, especially for mild to moderate renal insufficiency.

Antiretrovirals and the kidney in current clinical practice: renal pharmacokinetics, alterations of renal function and renal toxicity.

Assessment of renal function in HIV-positive patients is of increasing importance in the context of ageing and associated comorbidities. Exposure to nephrotoxic medications is widespread, and several commonly used antiretroviral drugs have nephrotoxic potential. Moreover, specific antiretrovirals inhibit renal tubular transporters resulting in the potential for drug-drug interactions as well as increases in serum creatinine concentrations, which affect estimates of glomerular filtration rate in the absence of changes in actual glomerular filtration rate. This review explores the effects of antiretroviral therapy on the kidney and offers an understanding of mechanisms that lead to apparent and real changes in renal function.

Abordagem da glicosúria renal na criança: a propósito de um caso clínico

Introduction : The accidental finding of glycosuria should lead to the exclusion of diabetes mellitus. In the absence of hyperglycemia, glycosuria is probably of renal origin. It can be isolated, as in familiar renal glycosuria, or it can be part of a hereditary tubular disorder such as Fanconi -Bickel syndrome or associated with an acquired tubular dysfunction. The renal and tubular function should be investigated. Case report : The authors describe the case of a previously healthy five -year old child with persistent glycosuria of renal cause. The investigation showed the coexistence of elevated renal excretion of glycine. Discussion : Familiar renal glycosuria and hyperglycinuria are caused by genetic defects in different renal tubular membrane transporters. The rare association of glycosuria and glycinuria was only described in one family in the 1960’s.The authors discuss the possible pathophysiologic mechanisms of this association and the importance of studying other tubulopathies in a child with glycosuria as it has prognostic and clinical management implications.

Index of Suspicion

The reader is encouraged to write possible diagnoses for each case before turning to the discussion. We invite readers to contribute case presentations and discussions. Please inquire first by contacting Dr. Deepak Kamat at DKamat@med.wayne.edu. An 18-year-old male with a 3-year history of alcohol abuse is referred from a rehabilitation center for fever, nausea, and nonbloody diarrhea for 3 days. Six weeks ago, he enrolled in an alcohol rehabilitation program and stopped drinking alcohol. Three weeks later, he noticed yellowing of his eyes and skin, difficulty sleeping, and dyspnea. On examination, his temperature is 100.6°F (38.1°C), blood pressure is 99/62 mm Hg, pulse is 124 beats per minute, and respiratory rate is 24 breaths per minute. He is slow to answer questions. There is no asterixis. He appears thin and jaundiced with enlarged parotid glands. Decreased breath sounds are noted on the right. A tender, enlarged liver and mild abdominal distension are noted. Trace bilateral lower-extremity edema is present. No stigmata of chronic liver disease are found. Laboratory findings reveal the following: white blood cell count, 25,600/μL (25.6 × 109/L) (87% neutrophils); hemoglobin, 8.2 g/dL (82 g/L); mean corpuscular volume, 106 fL; platelets, 40 × 103/μL (40 × 109/L); sodium, 135 mEq/L (135 mmol/L); potassium, 3.5 mEq/L (3.5 mmol/L); chloride, 106 mEq/L (106 mmol/L); bicarbonate, 15 mEq/L (15 mmol/L); blood urea nitrogen, 24 mg/dL (8.6 mmol/L); creatinine, 1.01 mg/dL (89 μmol/L); glucose, 118 mg/dL (6.6 mmol/L); alkaline phosphatase, 182 U/L; aspartate aminotransferase (AST), 194 U/L; alanine aminotransferase (ALT), 71 U/L; total bilirubin, 11.8 mg/dL (201.8 μmol/L); direct bilirubin, 7.3 mg/dL (124.9 μmol/L); albumin, 2.7 g/dL (27 g/L); prothrombin time, 19.2 seconds; and international normalized ratio, 1.4. Ethanol and acetaminophen were not detected in the serum. A chest radiograph reveals a right pleural effusion …

The kidney and uremic toxin removal: glomerulus or tubule?

Chronic kidney disease (CKD) is a condition that affects approximately 10% of the adult population in developed countries. In patients with CKD adequate renal clearance is compromised, resulting in the accumulation of a plethora of uremic solutes. These uremic retention solutes, also known as uremic toxins, are a heterogeneous group of organic compounds, many are too large to be filtered (middle molecules) or are protein-bound. Tubular secretion shifts the binding and allows for active secretion of such solutes. To mediate urinary solute excretion, renal proximal tubules are equipped with a range of transporters that cooperate in basolateral uptake and luminal excretion. These putative uremic toxins are poorly filtered across dialysis membranes because they are protein bound and current dialysis therapy does not correct the full spectrum of uremic toxicity. Residual renal function, which may represent an important contribution of solutes secreted by the proximal tubule rather than unreabsorbed filtrate, is an important predictor of survival of CKD patients. Many of the transporters that mediate the renal excretion of uremic retention solutes were first recognized as mediators of drug trafficking and drug-drug interactions, and a considerable amount of literature concerning the actions of these transporters antedates the recognition of their importance in the proximal renal tubular transport of uremic retention solutes. These transporters include members belonging to the organic cation/anion/zwitterion solute carrier family, such as the organic anion transporters (OAT)1, OAT3, and OATP4C1, and to the adenosine triphosphate binding cassette superfamily of transmembrane transporters, including the multidrug resistance proteins and breast cancer resistance protein. This article draws on this body of information to describe the renal tubular clearance mechanisms for uremic toxins, as well as the intracellular events associated with their accumulation, involving activation of the aryl hydrocarbon receptor, disturbance of mitochondrial functioning, and competition with metabolizing enzymes.

Regulatory roles of nitric oxide and angiotensin II on renal tubular transport.

Renal tubules regulate blood pressure and humoral homeostasis. Mediators that play a significant role in regulating the transport of solutes and water include angiotensin II (AngII) and nitric oxide (NO). AngIIcan significantly raise blood pressure via effects on the heart, vasculature, and renal tubules. AngII generally stimulates sodium reabsorption by triggering sodium and fluid retention in almost all segments of renal tubules. Stimulation of renal proximal tubule (PT) transport is thought to be essential for AngII-mediated hypertension. However, AngII has a biphasic effect on in vitro PT transport in mice, rats, and rabbits: stimulation at low concentrations and inhibition at high concentrations. On the other hand, NO is generally thought to inhibit renal tubular transport. In PTs, NO seems to be involved in the inhibitory effect of AngII. A recent study reports a surprising finding: AngII has a monophasic stimulatory effect on human PT transport. Detailed analysis of signalling mechanisms indicates that in contrast to other species, the human NO/guanosine 3',5'-cyclic monophosphate/extracellular signal-regulated kinase pathway seems to mediate this effect of Ang II on PT transport. In this review we will discuss recent progress in understanding the effects of AngII and NO on renal tubular transport.

Hypoxia-inducible Factor-1α (HIF-1α) Protein Diminishes Sodium Glucose Transport 1 (SGLT1) and SGLT2 Protein Expression in Renal Epithelial Tubular Cells (LLC-PK1) under Hypoxia

In this work, we demonstrated the regulation of glucose transporters by hypoxia inducible factor-1α (HIF-1α) activation in renal epithelial cells. LLC-PK1 monolayers were incubated for 1, 3, 6, or 12 h with 0% or 5% O2 or 300 μm cobalt (CoCl2). We evaluated the effects of hypoxia on the mRNA and protein expression of HIF-1α and of the glucose transporters SGLT1, SGLT2, and GLUT1. The data showed an increase in HIF-1α mRNA and protein expression under the three evaluated conditions (p < 0.05 versus t = 0). An increase in GLUT1 mRNA (12 h) and protein expression (at 3, 6, and 12 h) was observed (p < 0.05 versus t = 0). SGLT1 and SGLT2 mRNA and protein expression decreased under the three evaluated conditions (p < 0.05 versus t = 0). In conclusion, our results suggest a clear decrease in the expression of the glucose transporters SGLT1 and SGLT2 under hypoxic conditions which implies a possible correlation with increased expression of HIF-1α.