Renal tubular response to titanium dioxide nanoparticles exposure.

Titatinum dioxide nanoparticles (TiO2-NPs) are frequently used in several areas. Titanium alloys are employed in orthopedic and odontological surgery (such as hip, knee, and teeth implants). To evaluate the potential acute toxic effects of titanium pieces implantations and in other sources that allow the systemic delivery of titanium, parenteral routes of TiO2-NPs administration should be taken into account. The present study evaluated the impact of subcutaneous administration of TiO2-NPs on renal function and structure in rats. Animals were exposed to a dose of 50 mg/kg b.w., s.c. and sacrificed after 48 h. Titanium levels were detected in urine (135 ± 6 ηg/mL) and in renal tissue (502 ± 40 ηg/g) employing inductively coupled plasma mass spectrometry. An increase in alkaline phosphatase activity, total protein levels, and glucose concentrations was observed in urine from treated rats suggesting injury in proximal tubule cells. In parallel, histopathological studies showed tubular dilatation and cellular desquamation in these nephron segments. In summary, this study demonstrates that subcutaneous administration of TiO2-NPs causes acute nephrotoxicity evidenced by functional and histological alterations in proximal tubule cells. This fact deserves to be mainly considered when humans are exposed directly or indirectly to TiO2-NPs sources that cause the systemic delivery of titanium.

Novel Finding of Urinary Erythropoietin as an Early Biomarker of Cisplatin-Induced Nephrotoxicity.

Cisplatin is a chemotherapeutic drug used to treat a great variety of solid tumors. Its dose is commonly limited by its nephrotoxicity, manifested as acute kidney injury (AKI). Erythropoietin (Epo) is a glycoprotein hormone that regulates the production of red blood cells. This study was performed to evaluate the presence of endogenous Epo in male Wistar rat urine and to analyse changes in urinary Epo levels in response to cisplatin- induced AKI. Dose-dependent studies and time-dependent experiments were performed to evaluate changes in urea nitrogen and creatinine in plasma as well as Epo, neutrophil gelatinase-associated lipocalin (NGAL), alkaline phosphatase (AP) activity, creatinine and total proteins in urine at 2 days post-dosing. Rats received 2, 5 or 10 mg/kg b.w., i.p. of cisplatin. At 5 mg/kg b.w., i.p. cisplatin, significant increases in urinary Epo were detected. Significant increases in urea nitrogen and creatinine in plasma, NGAL, AP, proteins, and Epo were observed in urine from rats that received 10 mg/kg b.w., i.p. of cisplatin. In the time-dependent experiments, rats were injected with a dose of 5 mg/kg b.w., i.p. of cisplatin, and sampling occurred 2, 4, and 14 days post-dosing. In these animals, there were significant increases in urea nitrogen and creatinine in plasma and total proteins, AP activity, Epo, and NGAL in urine on day 4. Urinary Epo was also detected on day 2. Taken together, these findings provide weight of evidence for urinary Epo as a promising early biomarker of cisplatin-induced AKI in male rats.

Renal expression and urinary excretion of aquaporin-2 in postobstructive uropathy in rats.

This work assessed the time course of water renal management together with aquaporin-2 (AQP2) kidney expression and urinary AQP2 levels (AQP2u) in obstructive nephropathy. Adult male Wistar rats were monitored after 1, 2, and 7 days of bilateral ureteral release (bilateral ureteral obstruction (BUO); BUO-1, BUO-2 and BUO-7). Renal water handling was evaluated using conventional clearance techniques. AQP2 levels were assessed by immunoblotting and immunohistochemical techniques. AQP2 expression in apical membranes was downregulated in BUO-1 rats and upregulated both in BUO-2 and BUO-7 animals. AQP2 protein expression in whole cell lysate fraction from kidney cortex and medulla were significantly decreased in all the experimental groups. Concomitantly, mRNA levels of AQP2 decreased in renal medulla of all groups and in renal cortex from BUO-1; however, in renal cortex from BUO-2 and BUO-7 a recovery and an increase in the level of AQP2 mRNA were, respectively, observed. BUO-7 group showed a significant increase in AQP2u. The alterations observed in apical membranes AQP2 expression could explain, at least in part, the evolution time of water kidney management in the postobstructive phase of BUO. Additionally, the AQP2u increase after 7 days of ureteral release may be postulated as a biomarker of improvement in the kidney function.

Hepatic and renal expression of Oatp1 in obstructive uropathy. First detection of Oatp1 in urine, a potential biomarker.

Obstructive renal diseases affect renal function and kidney integrity. Nevertheless, little is known about its systemic or extra-renal effects. The organic anion transporting polypeptide 1 (Oatp1) is a carrier expressed in liver and kidneys. In this study, the hepatic and renal expression of Oatp1 was evaluated in rats with obstructive nephropathy. Moreover, the urinary excretion of Oatp1 (Oatp1u ) was evaluated as a potential biomarker for this pathology. Male Wistar rats with bilateral ureteral obstruction for 5 hours (BUO5), 24 hours (BUO24) or sham operated were used. After 24 hours of ureteral releasing, liver and kidney functional parameters, histopathology, Oatp1 tissular expression and Oatp1u were evaluated. For Oatp1u evaluation two groups were added; BUO1 and BUO2 (1 and 2 hours of ureteral obstruction, respectively). Both liver and kidney functional parameters and histopathological studies showed alterations in BUO5 and BUO24. In hepatic homogenates, Oatp1 significantly decreased in BUO groups and in total liver membranes no modifications were observed. In renal homogenates, Oatp1 significantly decreased in BUO groups, but in apical kidney membranes, its expression was increased. Oatp1u was only detected in BUO groups, even in those (BUO1, BUO2) in which no alterations in the traditional parameters of renal function were observed. Modulations in liver and renal expression of Oatp1 could be an organism strategy to attenuate the effects of the disease and an attempt to maintain the complex organ cross-talk between liver and kidneys. Oatp1u could be a new, early and specific biomarker of obstructive nephropathy.

Utility of urinary organic anion transporter 5 as an early biomarker of obstructive nephropathy.

Ureteral obstruction is a relevant cause of kidney damage. The traditional parameters used in clinical practice for the detection of renal injury are insensitive and non-specific for the diagnosis of obstructive renal disease. The organic anion transporter 5 (Oat5) is a carrier expressed exclusively in the kidney. In this study, the Oat5 urinary excretion (Oat5u ) was evaluated as a potential biomarker of obstructive nephropathy, comparing it with traditional markers of renal function and with neutrophil gelatinase-associated lipocalin in urine (NGALu ), a more recent biomarker of renal pathology. Bilateral ureteral obstruction (BUO) was induced in male Wistar rats, by complete ligation of ureters for 1 hour (BUO1), 2 hours (BUO2), 5 hours (BUO5), or 24 hours (BUO24). After 24 hours of ureteral releasing, urea and creatinine plasma concentrations, creatinine clearance, urinary total proteins, urinary glucose, and alkaline phosphatase activities in urine were evaluated. Oat5 and NGAL levels were assessed in urine samples by immunoblotting. All parameters of renal function were altered in the BUO24 and some also in BUO5, while the Oat5u increased in all of the experimental groups analyzed. After a long time of ureteral obstruction (BUO24), the urinary excretion of Oat5 markedly increased, in parallel with the alteration in the other parameters evaluated. Nevertheless, in BUO1 and BUO2, Oat5u appeared as the only parameter modified. Therefore, Oat5u could be proposed as a novel early biomarker of ureteral obstruction, with the additional potential to inform about the severity of the obstructive injury suffered by the kidney.

Altered Renal Expression of Relevant Clinical Drug Transporters in Different Models of Acute Uremia in Rats. Role of Urea Levels.

BACKGROUND/AIMS: Organic anion transporter 1 (Oat1) and 3 (Oat3) are organic anion transporters that play critical roles in the body disposition of numerous clinically important drugs. We investigated the effects of acute uremia on the renal expression of Oat1 and Oat3 in three in vivo experimental models of acute kidney injury (AKI): induced by ischemia, by ureteral obstruction and by the administration of HgCl2. We also evaluated the influence of urea in the expression of these transporters in proximal tubular cells suspensions. METHODS: Membranes were isolated from kidneys of each experimental group and from cell suspensions incubated with different urea concentrations. Oat1 and Oat3 expressions were performed by immunoblotting. RESULTS: A good correlation between uremia and the renal protein expression of Oat1 and Oat3 was observed in vivo. Moreover, the incubation of isolated proximal tubular cells with different concentrations of urea decreases protein expression of Oat1 and Oat3 in plasma membranes in a dose-dependent manner. CONCLUSION: The more severe the renal failure, the more important is the decrease in protein expression of the transporters in renal membranes where they are functional. The in vitro study demonstrates that urea accounts, at least in part, for the decreased expression of Oat1 and Oat3 in proximal tubule plasma membranes.

Factors affecting distribution and abundance of Aspergillus section Nigri in vineyard soils from grapevine growing regions of Argentina.

BACKGROUND: Aspergillus species belonging to section Nigri are the main fungi responsible for ochratoxin (OTA) contamination in grapes and wine. These species live as saprophytes in the superficial layer of the vineyard soil. We evaluated the biodiversity of potentially ochratoxigenic strains of Aspergillus section Nigri isolated from vineyard soils from different grapevine growing regions of Argentina. The isolates were characterized by classical and molecular methods. A multiple correspondence analysis was performed to identify the overall correlation of the Aspergillus group distribution with environmental conditions, geographical characteristics and vineyard practices. RESULTS: Aspergillus niger aggregate was the prevalent group (71%) and A. carbonarius made up only 2%. Species discrimination by species-specific primers showed that in A. niger aggregate 89% were A. tubingensis; 97% of the uniseriate were A. japonicus/A. aculeatus. Isolates belonging to these groups were unable to produce OTA. Our results clearly demonstrate a strong association between presence of A. carbonarius, high average temperatures and drip irrigation. Precipitation levels appear as a secondary factor, and altitude, vineyard age, predominant species, grape variety or total fungal count showed no association with A. carbonarius. CONCLUSION: We demonstrated a low prevalence of ochratoxigenic species in vineyard soil from the grape-growing regions of Argentina.

Effect of Temperature, Water Activity and Incubation Time on Trichothecene Production by Fusarium cerealis Isolated from Durum Wheat Grains.

Fusarium cerealis is a causal agent of Fusarium Head Blight in wheat, and it produces both deoxynivalenol (DON) and nivalenol (NIV). Nevertheless, the effect of environmental factors on the growth and mycotoxin production of this species has not been studied so far. The objective of this study was to investigate the impact of environmental factors on the growth and mycotoxin production of F. cerealis strains. All strains were able to grow in a wide range of water activity (aW) and temperatures, but their mycotoxin production was influenced by strain and environmental factors. NIV was produced at high aW and temperatures, while optimal conditions for DON production were observed at low aW. Interestingly, some strains were able to simultaneously produce both toxins, which could pose a more significant risk for grain contamination.

Deletion of multispecific organic anion transporter Oat1/Slc22a6 protects against mercury-induced kidney injury.

The primary site of mercury-induced injury is the kidney due to uptake of the reactive Hg(2+)-conjugated organic anions in the proximal tubule. Here, we investigated the in vivo role of Oat1 (organic anion transporter 1; originally NKT (Lopez-Nieto, C. E., You, G., Bush, K. T., Barros, E. J., Beier, D. R., and Nigam, S. K. (1997) J. Biol. Chem. 272, 6471-6478)) in handling of known nephrotoxic doses of HgCl(2). Oat1 (Slc22a6) is a multispecific organic anion drug transporter that is expressed on the basolateral aspects of renal proximal tubule cells and that mediates the initial steps of elimination of a broad range of endogenous metabolites and commonly prescribed pharmaceuticals. Mercury-induced nephrotoxicity was observed in a wild-type model. We then used the Oat1 knock-out to determine in vivo whether the renal injury effects of mercury are mediated by Oat1. Most of the renal injury (both histologically and biochemically as measured by blood urea nitrogen and creatinine) was abolished following HgCl(2) treatment of Oat1 knock-outs. Thus, acute kidney injury by HgCl(2) was found to be mediated mainly by Oat1. Our findings raise the possibility that pharmacological modulation of the expression and/or function of Oat1 might be an effective therapeutic strategy for reducing renal injury by mercury. This is one of the most striking phenotypes so far identified in the Oat1 knock-out. (Eraly, S. A., Vallon, V., Vaughn, D. A., Gangoiti, J. A., Richter, K., Nagle, M., Monte, J. C., Rieg, T., Truong, D. M., Long, J. M., Barshop, B. A., Kaler, G., and Nigam, S. K. (2006) J. Biol. Chem. 281, 5072-5083).

Gender related differences in kidney injury induced by mercury.

The aim of this study was to determine if there are sex-related differences in the acute kidney injury induced by HgCl(2) since female rats express lower levels of renal Oat1 and Oat3 (transporters involved in renal uptake of mercury) as compared with males. Control males and females and Hg-treated male and female Wistar rats were employed. Animals were treated with HgCl(2) (4 mg/kg body weight (b.w.), intraperitoneal (i.p.)) 18 h before the experiments. HgCl(2) induced renal impairment both in male and female rats. However, female rats showed a lower renal impairment than male rats. The observed increase in kidney weight/body weight ratio seen in male and female rats following HgCl(2) treatment was less in the female rats. Urine volume and creatinine clearance decreased and Oat5 urinary excretion increased in both males and females, but to a lesser degree in the latter. Urinary alkaline phosphatase (AP) activity and histological parameters were modified in male but not in female rats after HgCl(2) administration. These results indicate that the lower Oat1 and Oat3 expression in the kidney of females restricts Hg uptake into renal cells protecting them from this metal toxicity. These gender differences in renal injury induced by mercury are striking and also indicate that Oat1 and Oat3 are among the main transporters responsible for HgCl(2)-induced renal injury.

Fusarium chaquense, sp. nov, a novel type A trichothecene-producing species from native grasses in a wetland ecosystem in Argentina.

The Chaco wetland is among the most biologically diverse regions in Argentina. In collections of fungi from asymptomatic native grasses (Poaceae) from the wetlands, we identified isolates of Fusarium that were morphologically similar to F. armeniacum, but distinct from it by their production of abundant microconidia. All the isolates had identical, or nearly identical, partial sequences of TEF1 and RPB2. But they were distinct from reference sequences from F. armeniacum and Fusarium species closely related to it. Phylogenetic analysis of 34 full-length housekeeping gene sequences retrieved from whole genome sequences of three Chaco wetland isolates, 29 genes resolved the isolates as an exclusive clade within the F. sambucinum species complex. Based on results of the morphological and phylogenetic analysis, we concluded that the Chaco wetland isolates are a distinct and novel species, herein described as Fusarium chaquense, sp. nov., which is closely related to F. armeniacum. F. chaquense in culture can produce the trichothecenes T-2 and HT-2 toxin, neosolaniol, diacetoxyscirpenol, and monoacetoxyscirpenol, as well as beauvericin and the pigment aurofusarin. Genome sequence analysis also revealed the presence of three previously described loci required for trichothecene biosynthesis. This research represents the first study of Fusarium in a natural ecosystem in Argentina.

Renal and non-renal response of ABC and SLC transporters in chronic kidney disease.

INTRODUCTION: The solute carrier (SLC) and the ATP-binding cassette (ABC) transporter superfamilies play essential roles in the disposition of small molecules (endogenous metabolites, uremic toxins, drugs) in the blood, kidney, liver, intestine, and other organs. In chronic kidney disease (CKD), the loss of renal function is associated with altered function of remote organs. As renal function declines, many molecules accumulate in the plasma. Many studies now support the view that ABC and SLC transporters as well as drug metabolizing enzymes (DMEs) in renal and non-renal tissues are directly or indirectly affected by the presence of various types of uremic toxins, including those derived from the gut microbiome; this can lead to aberrant inter-organ communication. AREAS COVERED: Here, the expression, localization and/or function of various SLC and ABC transporters as well as DMEs in the kidney and other organs are discussed in the context of CKD and systemic pathophysiology. EXPERT OPINION: According to the Remote Sensing and Signaling Theory (RSST), a transporter and DME-centric network that optimizes local and systemic metabolism maintains homeostasis in the steady state and resets homeostasis following perturbations due to renal dysfunction. The implications of this view for pharmacotherapy of CKD are also discussed.

Ecophysiology of Fusarium chaquense a Novel Type A Trichothecene Producer Species Isolated from Natural Grasses.

Fusarium chaquense, a recently formally described novel species, has been identified as an T-2 toxin (T-2), HT-2 toxin (HT-2) and other toxins producer in natural grasses (Poaceae) from Argentina. The major objective of this study was to describe the effect of water activity (aW, 0.995, 0.98, 0.95, 0.93 and 0.91), temperature (15, 25 and 30 °C) and incubation time (5, 15 and 25 days) on growth and to evaluate the production of T-2, HT-2 toxins and beauvericin (BEA) by two F. chaquense strains in a grass-based media. The results showed a wide range of conditions for F. chaquense growth and mycotoxin production. Both strains had a maximum growth rate at the highest aW (0.995) and 25 °C. Regarding mycotoxin production, more T-2 than the other analysed mycotoxins were produced by the two strains. T-2 production was favoured at 0.995 aW and 30 °C, while HT-2 production at 0.98-0.95 aW and 15 °C. The maximum levels of BEA were produced at 0.995 aW and 25-30 °C. Two-dimensional profiles of aW by temperature interactions were obtained from these data in order to identify areas where conditions indicate a significant risk of mycotoxins accumulation on grass. For its versatility on growth and mycotoxin production in a wide range of aW and temperatures, F. chaquense would have an adaptive advantage over other Fusarium species, and this would explain its high frequency of isolation in natural grasses grown up in the Chaco wetlands.

A Rare Case of Traumatic Thyroid Gland Hypoperfusion/Devascularization After a Gunshot Wound Through the Neck: Computed Tomography Findings.

BACKGROUND The thyroid gland is rarely injured in cases of penetrating neck trauma. Computed tomography (CT) plays a central role in prompt evaluation of the extent of penetrating neck trauma and can demonstrate thyroid gland injury. The current literature on thyroid gland injury is limited mostly to blunt trauma, with little emphasis on findings seen on CT imaging. In the present case report, we focus on CT imaging findings of thyroid gland hypoperfusion/devascularization in a patient who had a gunshot wound injury through the base of his neck. CASE REPORT A 26-year-old man was transferred to our trauma center after experiencing multiple gunshot wounds, including one through the base of the neck. The bullet path through his neck was associated with enlargement/edema involving the right thyroid lobe, with an asymmetric decrease in enhancement involving the mid and superior aspects of the right thyroid lobe. Maximum-intensity-projection angiographic images of the vascular supply of the thyroid gland suggested an abrupt decrease in caliber close to the origin of the posterior glandular branch of the right superior thyroid artery. The findings favored vasospasm rather than an arterial injury, which led to hypoperfusion/devascularization of the upper pole of the right thyroid lobe. CONCLUSIONS Thyroid gland hypoperfusion/devascularization after a penetrating neck injury is rare. Recognition of CT imaging findings that favor post-traumatic organ hypoperfusion/devascularization is crucial for prompt management and to decrease morbidity in such cases.

Expression of kidney and liver bilitranslocase in response to acute biliary obstruction.

BACKGROUND/AIM: It has been recently demonstrated that acute obstructive jaundice is associated with modifications in the renal expression and function of organic anion transporters such as Oat1, Oat3, Oatp1 and Mrp2. This study examined the expression and function of bilitranslocase in liver and kidney from rats with bile duct ligation (BDL). METHODS: Bilitranslocase expression was evaluated in renal homogenates (H), renal basolateral plasma membranes (KBLM) and liver plasma membranes (LPM) by immunoblotting. Bilitranslocase function was studied by measuring the kinetic parameters of electrogenic bromosulfophthalein (BSP) uptake in KBLM and LPM by a spectrophotometric technique. RESULTS: An increased abundance of bilitranslocase in KBLM without modifications in renal H and in LPM from BDL rats was observed compared with Sham rats. BDL rats showed a higher V(max) for BSP uptake in KBLM. No differences between groups were observed for Michaelis-Menten parameters in LPM. CONCLUSION: The higher renal expression and function of bilitranslocase in renal basolateral membranes from rats with obstructive cholestasis might also contribute to the dramatic increase in BSP renal excretion observed in this experimental model. This would be another compensation mechanism to overcome the hepatic dysfunction in the elimination of organic anions.

Oat5 and NaDC1 protein abundance in kidney and urine after renal ischemic reperfusion injury.

The aim of this study was to evaluate the abundance of the organic anion transporter 5 (Oat5) and the sodium-dicarboxylate cotransporter 1 (NaDC1) in kidney and urine after renal ischemic reperfusion injury. Renal injury was induced in male Wistar rats by occlusion of both renal pedicles for 0 (Group Sham), 5 (Group I5R60), or 60 (Group I60R60) min. The studies were performed after 60 min of reperfusion. The expression of Oat5 and NaDC1 was evaluated by IHC and Western blotting. Oat5 and NaDC1 abundance and alkaline phosphatase activity (AP) were assayed in urine. A decreased expression in renal homogenates and apical membranes and an increase in urinary excretion of Oat5 and NaDC1 were observed in I60R60 rats, as well as alterations of other widely used parameters for renal dysfunction and injury (plasma creatinine, urinary AP activity, kidney weight, histological lesions). In contrast, in the I5R60 group, only an increase in urinary excretion of Oat5 and mild histopathological damage was detected. This is the first study on Oat5 and NaDC1 detection in urine. These results suggest that urinary excretion of Oat5 might be an early indicator of renal dysfunction, which is useful for detection of even minor alterations in renal structural and functional integrity.

Expression and function of Oat1 and Oat3 in rat kidney exposed to mercuric chloride.

This study was designed to evaluate the expression and function of the organic anion transporters, Oat1 and Oat3, in rats exposed to a nephrotoxic dose of HgCl(2). Oat1 protein expression increased in renal homogenates and decreased in renal basolateral membranes from HgCl(2) rats, while Oat3 protein abundance decreased in both kidney homogenates and basolateral membranes. The lower protein levels of Oat1 and Oat3 in basolateral membranes explain the lower uptake capacity for p-aminohippurate (in vitro assays) and the diminution of the systemic clearance of this organic anion (in vivo studies) observed in treated rats. Since both transporters mediate mercury access to the renal cells, their down-regulation in basolateral membranes might be a defensive mechanism developed by the cell to protect itself against mercury injury. The pharmacological modulation of the expression and/or the function of Oat1 and Oat3 might be an effective therapeutic strategy for reducing the nephrotoxicity of mercury.

Caveolin-2 in urine as a novel biomarker of renal recovery after cisplatin induced nephrotoxicity in rats.

Acute kidney injury (AKI) is a heterogeneous clinical syndrome with diverse outcomes. The recovery from AKI has prognostic importance. Little research has been done in order to find biomarkers that can predict recovery from AKI. Cav-2 is one of the main constituents of caveolae and is expressed in kidney. This study analyzed the time course of Cav-2 urinary excretion and renal expression in rats treated with cisplatin. Male Wistar rats were injected with cisplatin (5 mg/kg b.w., i.p.), and the studies were performed after 2, 4 and 14 days. Cav-2 abundance was evaluated in urine, in renal homogenates and in apical membranes by Western blotting. Cav-2 in urine was increased only 14 days after treatment, in the recovery phase of cisplatin-induced AKI. These results show that Cav-2 in urine could be useful as a biomarker of renal recovery, but not as an early biomarker of cisplatin-induced AKI. Cav-2 expression in total renal homogenates was not modified with treatment, but a down-regulation of Cav-2 in apical membranes was observed in treated animals. We hypothesize that Cav-2 internalizes into renal cells from their apical membrane in response to cisplatin, and regulates in this manner different signaling proteins involved in the physiopathology of renal damage.

Time course of organic anion excretion in rats with bilateral ureteral obstruction: role of organic anion transporters (Oat1 and Oat3).

BACKGROUND: Urinary tract obstruction is a common cause of renal failure. In this study, we evaluated the time course of P-aminohippurate (PAH) renal excretion and the cortical expression of organic anion transporters (Oat1 and Oat3) at 1 (BUO-1), 2 (BUO-2) and 7 (BUO-7) days after release of 24-hour bilateral ureteral obstruction (BUO) in the rat. METHODS: Conventional clearance technique, differential centrifugation, semiquantitative immunoblotting and immunohistochemical techniques have been employed. RESULTS: These studies showed that Oat1 and Oat3 in basolateral membranes were downregulated both at BUO-1 and BUO-2. Concomitantly, the rats developed a reduction in PAH renal elimination. In contrast, total recovery in PAH renal excretion and in the expression of Oat1 and Oat3 were observed at BUO-7, as compared with the sham group. A direct correlation was observed between the secretory clearance of PAH and Oat1 (r(2) = 0.88) and Oat3 (r(2) = 0.83) expression in basolateral membranes. CONCLUSION: These results indicate that the differential expression of organic anion transporters is one of the main molecular mechanisms contributing to the organic anion excretion modifications observed during the time course of obstructive nephropathy. This study provides evidence regarding the importance of adjusting the dose regimens of negatively charged drugs during the different time phases of this pathology.

Elimination of organic anions in response to an early stage of renal ischemia-reperfusion in the rat: role of basolateral plasma membrane transporters and cortical renal blood flow.

BACKGROUND/AIMS: The knowledge of molecular mechanisms determining drug pharmacokinetics in pathological states is relevant for the development of new therapeutic approaches. This study was undertaken to evaluate the cortical renal blood flow (cRBF) and the renal protein expression of the organic anion transporters (OAT1 and OAT3) in association with the elimination of organic anions in an early stage of renal ischemia-reperfusion. METHODS: Ischemic acute renal failure (ARF) was induced in adult male Wistar rats by occlusion of both renal pedicles during 60 min, followed by 60 min of reperfusion (ARF group). Pair-fed sham-operated rats served as controls. The renal protein expression of OAT1 and OAT3 was evaluated by immunohistochemistry techniques and by Western blotting in renal cortex homogenates and in basolateral plasma membranes. A pharmacokinetic study of p-aminohippurate (PAH, a prototypical organic anion) was performed. cRBF was determined using fluorescent microspheres. RESULTS: ARF rats displayed a significant decrease in systemic clearance and in renal excretion of PAH. OAT1 and OAT3 protein abundance showed a statistically significant reduction both in homogenates and in basolateral plasma membranes from ARF rats. Immunohistochemical studies confirmed the changes in the cortical renal expression of these transporters. ARF animals also showed a decrease in cRBF. CONCLUSIONS: The decrease in PAH elimination observed in an early stage of renal ischemia-reperfusion in male Wistar rats might be explained by the sum of the lower OAT1 and OAT3 expression in renal basolateral plasma membranes plus the decrease in cRBF. These findings might have significant implications in the development of novel pharmacological strategies to be applied in the initial stages of ischemic ARF.