G. Hotter

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Papers by G. Hotter

Carbonic Anhydrase Protects Fatty Liver Grafts against Ischemic Reperfusion Damage

PLOS ONE, 2015

Tubular Epithelial Cells Transfected With hHGF Counteracts Monocyte Chemotactic Protein-1 Up-regulation After Hypoxia/Reoxygenation Insult

Transplantation Proceedings, 2009

Acute kidney injury (AKI) which is mainly produced by nephrotoxic or ischemic insults is correlat... more Acute kidney injury (AKI) which is mainly produced by nephrotoxic or ischemic insults is correlated with a high mortality and morbidity. Proximal tubular epithelial cells (PTEC) play a major role. They are the main target of ischemia/reperfusion injury. PTECs have also been proposed as the effectors of AKI reversibility, but also as the creator of the inflammatory milieu: cytokine, chemokine, and complement expression. An important chemokine implicated in this process is monocyte chemotactic protein-1 (MCP-1) due to its ability to recruit and activate monocytes. Hepatocyte growth factor (HGF) is a pleiotropic factor with mitogenic, anti-apoptotic, and proliferative effects which has recently been studied for its anti-inflammatory and antifibrogenic effects. Our aim was to evaluate the potential inflammatory effect of hypoxia and reoxygenation on rat PTECs. We created a stable human HGF (hHGF) expressing PTEC line that emulated in vivo transfection and analyzed the role of this cell type in the induction and reversibility of AKI. Our results showed the efficiency of transfection with the hHGF gene to promote sustained expression of the protein in the medium (7627.13 Ϯ 1144.078 to 8211.3 Ϯ 795.37 pg/mL). When rat PTECs were under a hypoxia/reoxygenation insult, MCP-1 was highly overexpressed (4479.3 Ϯ 154.3 pg/mL of protein and 5.099 Ϯ 1.23 times control gene expression). Transfected cells abrogated this effect (288.7 Ϯ 13.5 pg/mL and 1.169 Ϯ 0.0759 times control). In conclusion, we observed that the hypoxia/reoxygenation insult stimulated MCP-1 protein secretion in PTECs and that PTECs which were stably transfected and overexpressing hHGF abrogated the inflammatory reaction mediated by hypoxia/ reoxygenation, being a suitable model for later studies.

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Lipocalin-2-induced renal regeneration depends on cytokines

AJP: Renal Physiology, 2008

This study investigated whether the renal regeneration occurring in the recovery phase of kidney ... more This study investigated whether the renal regeneration occurring in the recovery phase of kidney ischemia-reperfusion (I/R) is mediated by endogenously generated lipocalin-2 (Lcn2). A second objective was to examine whether Lcn2-mediated cell effects could be regulated by the inflammatory cytokines in the environment through their action on Lcn2 receptors (Lcn2R and megalin). Male Swiss mice were subjected to 30 min of renal ischemia with a reperfusion period of 24 h (early reperfusion, expected time for maximum inflammation) and 96 h (late reperfusion, expected time for maximum regeneration). Different experimental groups underwent I/R, I/R with iv anti-mouse Lcn2 monoclonal antibody injected during the early/inflammatory or late/recovery phase, and I/R with proinflammatory cytokine cocktail administration (recombinant mouse IL-1β, TNF-α, and IFN-γ). Compared with control nonischemic mice, the expression of three proliferation markers (stathmin, PCNA, and Ki-67, analyzed by quantit...

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The impact of arterialization on prostanoid generation after liver transplantation in the rat

Transplantation, Jul 27, 1994

Arterial reconstruction is not applied in most studies of hepatic transplantation. Differences in... more Arterial reconstruction is not applied in most studies of hepatic transplantation. Differences in some parameters related to the microcirculatory status, depending on whether the graft has been subjected to both arterial and venous or only venous reconstruction have been demonstrated. We have evaluated whether arterialization has an effect on the production of inflammatory event-related mediators such as eicosanoids and oxygen free radicals. For this purpose, we have measured tissue eicosanoid levels, lipid peroxidation, and superoxide dismutase activity in livers subjected to arterial and venous or only venous reconstruction. No changes were observed in lipid peroxidation or superoxide dismutase activity when single and double revascularization were compared. Prostacyclin and thromboxane metabolites showed increased levels after 24-hr preservation when only venous reconstruction was carried out. In contrast, these metabolites remained unaltered when double revascularization was per...

Arachidonate metabolism in ischemia-reperfusion associated with pancreas transplantation

Journal of Lipid Mediators and Cell Signalling, 1994

The implication of eicosanoid metabolism and its relationship with oxygen free radical production... more The implication of eicosanoid metabolism and its relationship with oxygen free radical production in the process of ischemia-reperfusion associated with rat pancreas transplantation has been explored in this study. For this purpose male Sprague-Dawley rats were classified as follows: group I, control animals not surgically manipulated; group II, pancreas transplantation, after 30 min preservation in UW solution; group III, pancreas transplantation after 12 h preservation under the same conditions; group IV, same as group III but with administration of SOD 5 min prior to organ revascularization. The results show post-transplantation increases in 6-keto-PGF1 alpha, TXB2, LTB4 and 12-HETE in pancreatic tissue independent of preservation time. The fact that SOD administration could reverse these increases even though an efficient xanthine oxidase irreversible inhibitor such as allopurinol was present in the preservation solution suggests that eicosanoid generation in the recipient rat w...

Thromboxane flux and urinary eicosanoids as an index of reperfusion injury in pancreas transplantation after different periods of cold storage

Transplantation Proceedings, 1988

Effect of a platelet-activating factor antagonist and desferrioxamine administration on eicosanoid production in rat pancreas transplantation

Transplantation, 1994

Eicosanoid metabolism and its relationship with platelet-activating factor and oxygen free radica... more Eicosanoid metabolism and its relationship with platelet-activating factor and oxygen free radical production in rat pancreas transplantation has been studied herein. Male Sprague-Dawley rats were classified in 4 experimental groups (n = 8 each) as follows: group 1, control; group 2, pancreas transplantation, after 12 hr of organ preservation in University of Wisconsin solution; group 3, same as group 2 with desferrioxamine administration before revascularization of the organ in the recipient rat; and group 4, same as group 3 with administration of a platelet-activating factor antagonist (BN-52021). The results show post-transplantation increases in eicosanoid production in pancreatic tissue. The fact that desferrioxamine and BN-52021 administration could reverse increases in thromboxane B2, leukotriene B4, and 12-hydroxyeicosatetraenoic acid but only BN-52021 affected 6-keto-PGF1 alpha levels suggests the existence of a close relationship between platelet-activating factor and oxyg...

Markers of early renal changes induced by industrial pollutants. I. Application to workers exposed to mercury vapour

British Journal of Industrial Medicine, 1993

Several markers of renal changes have been measured in a cohort of 50 workers exposed to elementa... more Several markers of renal changes have been measured in a cohort of 50 workers exposed to elemental mercury (Hg) and in 50 control workers. After application of selection criteria 44 exposed and 49 control workers were retained for the final statistical analysis. Exposed workers excreted on average 22 micrograms Hg/g creatinine and their mean duration of exposure was 11 years. Three types of renal markers were studied--namely, functional markers (creatinine and beta 2-microglobulin in serum, urinary proteins of low or high molecular weight); cytotoxicity markers (tubular antigens and enzymes in urine), and biochemical markers (eicosanoids, thromboxane, fibronectin, kallikrein, sialic acid, glycosaminoglycans in urine, red blood cell membrane negative charges). Several bloodborne indicators of polyclonal activation were also measured to test the hypothesis that an immune mechanism might be involved in the renal toxicity of elemental Hg. The main renal changes associated with exposure ...

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Beneficial effect of superoxide dismutase (SOD) on erythrocyte trapping and 6-keto-PGF1 alpha TxB2 ratio after ischemia-reperfusion in kidney transplantation

Transplantation Proceedings, 1990

Articles Multiparametric Monitoring of Ischemia-Reperfusion in Rat Kidney: Effect of Ischemic Preconditioning

ing tool for monitoring kidney ischemia and the changes induced by its therapeutic management. Is... more ing tool for monitoring kidney ischemia and the changes induced by its therapeutic management. Isch-emic preconditioning, that is, brief ischemic periods before sustained ischemia, has been shown to protect several organs, including the kidney, from ischemia-reperfusion injury. We tested whether the effect of preconditioning could be appraised by real-time mea-surement of parameters representative of tissue hypoxia. Methods. In a sample of pentobarbital-anesthetized and mechanically ventilated rats, we studied the effect of renal ischemic preconditioning (10-min ischemia and 10-min reflow interval) on subsequent ischemia-reperfusion (45 min and 60 min). Renal tissue electri-cal impedance, extracellular pH, and potassium con-

Altered levels of tissue and urinary prostacyclin in rats subjected to pancreas transplantation

Prostaglandins, 1991

Significant increases of TXB2 and PGE2 are reported to occur in pancreas transplantation. These i... more Significant increases of TXB2 and PGE2 are reported to occur in pancreas transplantation. These increases are prevented with scavengers of oxygen-free radicals. In this communication, we report on changes of prostacyclin metabolites such as tissue 6-keto prostaglandin F1 alpha and urinary 2,3-dinor 6-keto prostaglandin F1 alpha in rats subjected to pancreas transplantation after different periods of organ cold preservation ischemia as well as the effect of superoxide dismutase (SOD) on these changes. For this purpose, male Lewis rats were classified as follows: Group I, Control; Group II, syngenic pancreas transplantation after 15 min of organ preservation in Collins solution at 4 degrees C; Group III, same as II but with 12 hours of organ preservation; Group IV, same as III, but with SOD pretreatment. Results have shown significant posttransplantation increases of both tissue 6-keto PGF1 alpha and urinary 2, 3 dinor 6-keto PGF1 alpha, the latter being a useful marker to evaluate sy...

Prostanoids and free radicals in Cl4C-induced hepatotoxicity in rats: effect of astilbin

Prostaglandins, leukotrienes, and essential fatty acids, 1997

A beneficial effect of flavonoids in Cl(4)C-induced hepatoxicity in rats has been reported. In th... more A beneficial effect of flavonoids in Cl(4)C-induced hepatoxicity in rats has been reported. In this communication we have evaluated the protective effect of astilbin, an active flavonoid isolated from a crude extract of Hymenaea martiana, as well as its action on liver arachidonate metabolism in Cl(4)C-treated rats. The following groups of rats were studied: Group I = controls; Group II = Astilbine-treated animals (40 mg/Kg); Group III = Cl(4)C-treated at 1 ml/kg; Group IV = Astilbine + ClC4 and Group V = Vitamine E (50 mg/Kg) + Cl(4)C-treated animals. Histological findings, superoxide dismutase activity, lipoperoxides and prostanoid profiling studies revealed that the hepatoprotective effect of astilbine was higher than that of vitamin E. Astilbine was capable to restore lipoperoxides and tissue prostanoids to basal values.

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Differential effect of nitric oxide inhibition as a function of preservation period in pancreas transplantation

Digestive diseases and sciences, 1997

The role of nitric oxide, produced during reperfusion as a function of preservation time, in the ... more The role of nitric oxide, produced during reperfusion as a function of preservation time, in the development of the inflammatory process in pancreas transplantation has been explored. For this purpose, the effect of nitric oxide synthase inhibition, as well as 6-keto-prostaglandin F1alpha, leukotriene B4, and lipoperoxidation levels were evaluated in an experimental model of rat pancreas transplantation after different periods of cold preservation. The results show posttransplantation increases in 6-keto-prostaglandin F1alpha, leukotriene B4, and lipoperoxidation levels in pancreatic tissue and in plasma lipase. When ischemia was induced for 30 min, nitric oxide synthase inhibition prevented these increases, and L-arginine was able to reverse this effect. By contrast, nitric oxide synthase inhibition has no effect when ischemia was prolonged for 12 hr. In summary, this study suggests that, during reperfusion, nitric oxide modulates 6-keto-prostaglandin F1alpha synthesis, lipoperoxid...

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Urinary prostanoids excretion in kidney transplantation: its relationship to acute rejection and cyclosporine-induced nephrotoxicity

Transplantation proceedings, 1994

Nephron target sites in chronic exposure to lead

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 1994

With established urinary markers of kidney integrity the early renal effects of lead have previou... more With established urinary markers of kidney integrity the early renal effects of lead have previously been considered to be mainly tubular or tubulointerstitial. In a cross-sectional study on 81 male lead-exposed workers and 45 age-matched controls (median blood lead concentrations 2.03 and 0.34 mumol/l respectively) not only well-established but also new urinary markers of renal integrity preferentially or exclusively located along the different nephron segments were analysed. Markers related to the glomerulus were 6-keto-prostaglandin 1 alpha, thromboxane B2, mainly produced in the glomerulus, and the extracellular matrix protein fibronectin. Markers of the proximal tubule were the brush-border antigens BBA, BB50, and HF5 and the intestinal alkaline phosphatase. Prostaglandin E2 and F2 alpha, preferentially synthesized in the collecting duct and medullary interstitial cells, served as markers of these more distal nephron segments. In contrast to previous studies on the early phase ...

A bradykinin antagonist inhibited nitric oxide generation and thromboxane biosynthesis in acute pancreatitis

Prostaglandins, 1995

The effect of bradykinin on nitric oxide generation and eicosanoid production in the early stage ... more The effect of bradykinin on nitric oxide generation and eicosanoid production in the early stage of an experimental model of acute necrotizing pancreatitis induced by sodium taurocholate has been evaluated. We have compared the effect of administering a long-acting bradykinin antagonist, HOE 140, and an inhibitor of nitric oxide synthase, NG-nitro-L-arginine methyl esther L-NAME) on pancreatic prostanoid synthesis. Plasma lipase levels were increased after acute pancreatitis induction, and reduced after HOE 140 or L-NAME administration. Nitric oxide production and thromboxane B2 levels were increased after pancreatitis induction and the increases were reduced by L-NAME or HOE 140 administration. In contrast, increased prostacyclin production, reflected as 6-keto-PGF1 alpha levels, was not modified by L-NAME or HOE 140. Bradykinin seems to be involved in nitric oxide and thromboxane synthesis during the initial phases of acute necrohemorrhagic pancreatitis.

Prostaglandin E2 and thromboxane B2 levels in rats subjected to pancreas transplantation

Prostaglandins, 1990

This work undertakes the study of changes in urinary, plasmatic and tissue levels of Thromboxane ... more This work undertakes the study of changes in urinary, plasmatic and tissue levels of Thromboxane B2 (TXB2) as well as in tissue Prostaglandin E2 (PGE2) after pancreas transplantation and the effect of superoxide dismutase (SOD) on these changes. For this purpose, streptozotocine induced diabetic rats were subjected to pancreas transplantation. Experimental groups were classified as follows: Group I: Control; Group II: Animals subjected to 15 min of pancreas arterial flow occlusion followed by reperfusion; Group III: Syngenic pancreas transplantation after 12 hours of organ preservation; Group IV: Same as III, but with additional SOD (13 mg/kg) pretreatment. The results indicate that significant increases of PGE2 and TXB2 levels occur as a consequence of the surgical removal, preservation and implantation of the organ. For TXB2 these increases, immediate in plasma and tissue, are not detected in urine until 24 hours after transplantation of the pancreas. The release of TXB2 and PGE2 ...

Beneficial effect of superoxide dismutase (SOD) on erythrocyte trapping and 6-keto-PGF1 alpha TxB2 ratio after ischemia-reperfusion in kidney transplantation

Transplantation proceedings, 1990

Pancreas prostanoid production in ischemia and reperfusion

Prostaglandins, 1992

This study was carried out to investigate the proportion of the 6-keto prostaglandin F1 alpha (6-... more This study was carried out to investigate the proportion of the 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) and thromboxane B2 (TXB2) alteration that is due to ischemia in pancreas transplantation against the proportion due to reperfusion. For this purpose, Lewis rats were divided in three experimental groups: Group I = Control, Group II = Donor pancreas subjected to 15 minutes of cold ischemia, Group III = Same as group II but pancreas were transplanted to the recipient individual and then subjected to reperfusion. The results indicate that increases in pancreas 6-keto PGF1 alpha occur as a consequence of cold ischemia while TXB2 remains unchanged. When blood flow was restored, 6-keto PGF1 alpha remained unchanged compared to the ischemic group while pancreatic levels of TXB2 were significantly increased. These results suggest a different induction of prostanoid metabolism during ischemia and reperfusion in pancreatic tissue.

Cisplatin upregulates mitochondrial nitric oxide synthase and peroxynitrite formation to promote renal injury

Toxicology and Applied Pharmacology, 2009

The mitochondria are a critical target for cisplatin-associated nephrotoxicity. Though nitric oxi... more The mitochondria are a critical target for cisplatin-associated nephrotoxicity. Though nitric oxide formation has been implicated in the toxicity of cisplatin, this formation has not so far been related to a possible activation of mitochondrial nitric oxide synthase (mNOS). We show here that the upregulation of oxide mNOS and peroxynitrite formation in cisplatin treatment are key events that influence the development of the harmful parameters described in cisplatin-associated kidney failure. We confirm this by isolating the mitochondrial fraction of the kidney and across different access routes such as the use of a specific inhibitor of neuronal NOS, L-NPA, a peroxynitrite scavenger, FeTMPyP, and a peroxynitrite donor, SIN-1. The in vitro studies corroborated the information obtained in the in vivo experiments. The administration of cisplatin reveals a clear upregulation in the transcription of neuronal NOS and an increase in the levels of nitrites in the mitochondrial fractions of the kidneys. The upregulated transcription directly affects the cytoskeleton structure and the apoptosis. The inhibition of neuronal NOS reduces the levels of nitrites, cell death, and cytoskeleton derangement. Peroxynitrite is involved in the mechanism promoting the NOS transcription. In addition, in controls SIN-1 imitates the effects of cisplatin. In summary, we demonstrate that upregulation of mNOS in cisplatin treatment is a key component in both the initiation and the spread of cisplatin-associated damage in the kidney. Furthermore, peroxynitrite formation is directly involved in this process.