Instituto Reina Sofia Of Investigacion Nefrologica

Hoyos de Miguel Muñoz, Spain

Instituto Reina Sofia Of Investigacion Nefrologica

Hoyos de Miguel Muñoz, Spain
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Sancho-Martinez S.M.,University of Salamanca | Sancho-Martinez S.M.,Instituto Reina Sofia Of Investigacion Nefrologica | Piedrafita F.J.,Torrey Pines Institute for Molecular Studies | Cannata-Andia J.B.,University of Oviedo | And 5 more authors.
Toxicological Sciences | Year: 2011

Cisplatin is a chemotherapeutic drug whose cytotoxicity is key to its therapeutic and side effects. Nephrotoxicity, mainly due to renal tubular injury, poses its most important therapeutic limitation. Tubular necrosis is derived from epithelial cell death by apoptosis and necrosis in the proximal and distal tubuli. The mode of cell death has been related to drug concentration, with necrosis occurring with high concentrations and apoptosis with lower concentrations. To fully understand the toxic effects of cisplatin to potentially improve its pharmaco-toxicological profile, it is necessary to unravel the cellular events and signaling pathways implicated in the appearance of both modes of cell death. We used cultured human lymphoma and renal tubule cells to investigate the biochemical and phenotypic characteristics of the death mode induced by increasing concentrations of cisplatin. Our results indicate that pronecrotic concentrations of cisplatin early activate the apoptotic machinery, which is in turn directly blocked by cisplatin at the level of effector caspases. Aborted apoptosis induces a death phenotype lacking some typical characteristics of this process, which more closely resembles necrosis. Furthermore, unidentified Bcl-2- and mitochondriaindependent pathways are induced by pronecrotic and not by proapoptotic concentrations of cisplatin. Cisplatin-induced cell necrosis is the result of an aborted apoptosis at the level of effector caspases. Yet, Bcl-2-independent effects lead to cell death, which may pose potential targets for pharmacological intervention aimed at reducing cisplatin nephrotoxicity. © The Author 2011. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.

Quiros Y.,University of Salamanca | Quiros Y.,Instituto Reina Sofia Of Investigacion Nefrologica | Quiros Y.,Bio inRen S.L. | Vicente-Vicente L.,University of Salamanca | And 8 more authors.
Toxicological Sciences | Year: 2011

Gentamicin is an aminoglycoside antibiotic widely used against infections by Gram-negative microorganisms. Nephrotoxicity is the main limitation to its therapeutic efficacy. Gentamicin nephrotoxicity occurs in 10-20% of therapeutic regimes. A central aspect of gentamicin nephrotoxicity is its tubular effect, which may range from a mere loss of the brush border in epithelial cells to an overt tubular necrosis. Tubular cytotoxicity is the consequence of many interconnected actions, triggered by drug accumulation in epithelial tubular cells. Accumulation results from the presence of the endocytic receptor complex formed by megalin and cubulin, which transports proteins and organic cations inside the cells. Gentamicin then accesses and accumulates in the endosomal compartment, the Golgi and endoplasmic reticulum (ER), causes ER stress, and unleashes the unfolded protein response. An excessive concentration of the drug over an undetermined threshold destabilizes intracellular membranes and the drug redistributes through the cytosol. It then acts on mitochondria to unleash the intrinsic pathway of apoptosis. In addition, lysosomal cathepsins lose confinement and, depending on their new cytosolic concentration, they contribute to the activation of apoptosis or produce a massive proteolysis. However, other effects of gentamicin have also been linked to cell death, such as phospholipidosis, oxidative stress, extracellular calcium-sensing receptor stimulation, and energetic catastrophe. Besides, indirect effects of gentamicin, such as reduced renal blood flow and inflammation, may also contribute or amplify its cytotoxicity. The purpose of this review was to critically integrate all these effects and discuss their relative contribution to tubular cell death. © The Author 2010. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.

Garcia-Martinez R.,University College London | Caraceni P.,University of Bologna | Bernardi M.,University of Bologna | Gines P.,University of Barcelona | And 8 more authors.
Hepatology | Year: 2013

Since the introduction of human serum albumin as a plasma expander in the 1940s, considerable research has allowed a better understanding of its biochemical properties and potential clinical benefits. Albumin has a complex structure, which is responsible for a variety of biological functions. In disease, the albumin molecule is susceptible to modifications that may alter its biological activity. During the last decades, different methods to measure albumin function have been developed. Recent studies have shown that not only albumin concentration but also albumin function is reduced in liver failure. This observation led to the concept of effective albumin concentration, which represents the fact that plasma albumin concentration does not reflect its function. Indeed, in liver disease albumin function is several times less than its concentration. In patients with cirrhosis, albumin infusion reduces mortality in patients with spontaneous bacterial peritonitis and improves outcome following large volume paracentesis. In combination with vasoconstrictors, albumin is useful in the management of patients with hepatorenal syndrome. Its role is being investigated in a large number of indications, which rely on its volume and nonvolume expansion functions such as stroke, severe sepsis, Alzheimer's disease, malaria, burns, and ovarian hyperstimulation syndrome. This review explores the above concepts, reviews the available evidence for the use of albumin in liver diseases, defines therapeutic limitations, and explores the challenges that should be addressed in future research. © 2013 American Association for the Study of Liver Diseases.

Fernandez-Fernandez B.,Diabetes and Vascular Research Laboratory | Ortiz A.,Instituto Reina Sofia Of Investigacion Nefrologica | Gomez-Guerrero C.,Diabetes and Vascular Research Laboratory | Egido J.,Autonomous University of Madrid
Nature Reviews Nephrology | Year: 2014

Despite improvements in glycaemic and blood pressure control, and the efficacy of renin-angiotensin system (RAS) blockade for proteinuria reduction, diabetic nephropathy is the most frequent cause of end-stage renal disease in developed countries. This finding is consistent with the hypothesis that key pathogenetic mechanisms leading to progression of renal disease are not modified or inactivated by current therapeutic approaches. Although extensive research has elucidated molecular signalling mechanisms that are involved in progression of diabetic kidney disease, a number of high-profile clinical trials of potentially nephroprotective agents have failed, highlighting an insufficient understanding of pathogenic pathways. These include trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced-stage disease. Various strategies based on encouraging data from preclinical studies that showed renoprotective effects of receptor antagonists, neutralizing antibodies, kinase inhibitors, small compounds and peptide-based technologies are currently been tested in randomized controlled trials. Phase II clinical trials are investigating approaches targeting inflammation, fibrosis and signalling pathways. However, only one trial that aims to provide evidence for marketing approval of a potentially renoprotective drug (atrasentan) is underway - further research into the potential nephroprotective effects of novel glucose-lowering agents is required. © 2014 Macmillan Publishers Limited.

Nez R.,University of Salamanca | Nez R.,Instituto Reina Sofia Of Investigacion Nefrologica | Sancho-Martinez S.M.,University of Salamanca | Sancho-Martinez S.M.,Instituto Reina Sofia Of Investigacion Nefrologica | And 5 more authors.
Cell Death and Differentiation | Year: 2010

Apoptosis is a mode of cell death through which cells are dismantled and cell remains are packed into small, membrane-bound, sealed vesicles called apoptotic bodies, which are easy to erase by phagocytosis by neighbouring and immune system cells. The end point of the process is to cleanly eliminate damaged or unnecessary cells without disrupting the surrounding tissue or eliciting an inflammatory response. The apoptotic process involves a series of specific events including deoxyribonucleic acid and nuclear fragmentation, protease-driven cleavage of specific substrates, which inhibits key survival functions and reorganizes the cell's structure, externalization of molecules involved in phagocytosis, membrane blebbing and cell shrinkage. Apoptotic volume decrease (AVD) leading to cell shrinkage is a core event in the course of apoptosis, the biological meaning of which has not been clearly ascertained. In this article we argue that volume loss is a geometrical requisite for cell dismantling into apoptotic bodies. This is derived from the cell's volume-to-surface ratio. Indeed, package of the original cell volume into smaller membrane-sealed vesicles requires that either cell membrane surface increase or cell volume decrease. In this sense, AVD provides a reservoir of membrane surface for apoptotic body formation. The strategic situation of AVD in the time course of apoptosis is also discussed in the context of apoptotic body formation. © 2010 Macmillan Publishers Limited All rights reserved.

Lopez-Novoa J.M.,University of Salamanca | Lopez-Novoa J.M.,Instituto Reina Sofia Of Investigacion Nefrologica | Martinez-Salgado C.,Hospital Universitario Of Salamanca | Martinez-Salgado C.,University of Salamanca | And 5 more authors.
Pharmacology and Therapeutics | Year: 2010

It is estimated that over 10% of the adult population in developed countries have some degree of chronic kidney disease (CKD). CKD is a progressive and irreversible deterioration of the renal excretory function that results in implementation of renal replacement therapy in the form of dialysis or renal transplant, which may also lead to death. CKD poses a growing problem to society as the incidence of the disease increases at an annual rate of 8%, and consumes up to 2% of the global health expenditure. CKD is caused by a variety of factors including diabetes, hypertension, infection, reduced blood supply to the kidneys, obstruction of the urinary tract and genetic alterations. The nephropathies associated with some of these conditions have been modeled in animals, this being crucial to understanding their pathophysiological mechanism and assessing prospective treatments at the preclinical level. This article reviews and updates the pathophysiological knowledge acquired primarily from experimental models and human studies of CKD. It also highlights the common mechanism(s) underlying the most relevant chronic nephropathies which lead to the appearance of a progressive, common renal phenotype regardless of aetiology. Based on this knowledge, a therapeutic horizon for the treatment of CKD is described. Present therapy primarily based upon renin-angiotensin inhibition, future diagnostics and therapeutic perspectives based upon anti-inflammatory, anti-fibrotic and hemodynamic approaches, new drugs targeting specific signaling pathways, and advances in gene and cell therapies, are all elaborated. © 2010 Elsevier Inc.

Lopez-Hernandez F.J.,University of Salamanca | Lopez-Hernandez F.J.,Hospital Universitario Of Salamanca | Lopez-Hernandez F.J.,Instituto Reina Sofia Of Investigacion Nefrologica | Lopez-Novoa J.M.,University of Salamanca | Lopez-Novoa J.M.,Instituto Reina Sofia Of Investigacion Nefrologica
Cell and Tissue Research | Year: 2012

Transforming growth factor beta (TGF-β) has been recognized as an important mediator in the genesis of chronic kidney diseases (CKD), which are characterized by the accumulation of extracellular matrix (ECM) components in the glomeruli (glomerular fibrosis, glomerulosclerosis) and the tubular interstitium (tubulointerstitial fibrosis). Glomerulosclerosis is a major cause of glomerular filtration rate reduction in CKD and all three major glomerular cell types (podocytes or visceral epithelial cells, mesangial cells and endothelial cells) participate in the fibrotic process. TGF-βinduces (1) podocytopenia caused by podocyte apoptosis and detachment from the glomerular basement membrane; (2) mesangial expansion caused by mesangial cell hypertrophy, proliferation (and eventually apoptosis) and ECM synthesis; (3) endothelial to mesenchymal transition giving rise to glomerular myofibroblasts, a major source of ECM. TGF-βhas been shown to mediate several key tubular pathological events during CKD progression, namely fibroblast proliferation, epithelial to mesenchymal transition, tubular and fibroblast ECM production and epithelial cell death leading to tubular cell deletion and interstitial fibrosis. In this review, we re-examine the mechanisms involved in glomerulosclerosis and tubulointerstitial fibrosis and the way that TGF-βparticipates in renal fibrosis, renal parenchyma degeneration and loss of function associated with CKD. © Springer-Verlag 2011.

Sancho-Martinez S.M.,Institute Investigacion Biomedica Of Salamanca Ibsal | Sancho-Martinez S.M.,University of Salamanca | Sancho-Martinez S.M.,Instituto Reina Sofia Of Investigacion Nefrologica | Prieto-Garcia L.,Institute Investigacion Biomedica Of Salamanca Ibsal | And 11 more authors.
Pharmacology and Therapeutics | Year: 2012

Cisplatin is a chemotherapeutic drug widely used against a variety of cancers. Its clinical utility is severely limited by its toxicity, which mainly affects, but is not limited to, the inner ear and renal tubules. Cisplatin toxicity is determined by target tissue and cell accumulation, subcellular handling and trafficking through diverse subcellular structures, and interaction with macromolecules. Cisplatin accumulates and stresses different organelles from which delay signaling is activated, including mitochondria, lysosomes, the endoplasmic reticulum, the nucleus, the cell membrane and cytoskeleton, and can also be found in the cytosol. This article critically summarizes the available information in order to establish the connection among its known subcellular effects in a hierarchical and integrative framework. Cisplatin causes different types of cell death in a concentration-dependent manner. Knowledge of the events and signaling leading to the different phenotypes is also intertwined within the model, within the scope of the potential utility of this information in the improvement of the pharmacotoxicological profile of this drug. Perspectives for the key aspects that need to be addressed by future investigation are also outlined. © 2012 Elsevier Inc.

Garcia-Sanchez O.,University of Salamanca | Garcia-Sanchez O.,Instituto Reina Sofia Of Investigacion Nefrologica | Lopez-Hernandez F.J.,University of Salamanca | Lopez-Hernandez F.J.,Instituto Reina Sofia Of Investigacion Nefrologica | And 3 more authors.
Kidney International | Year: 2010

Transforming growth factor-β (TGF-β) is a cytokine known to participate in several processes related to the development of chronic kidney disease (CKD), including tubular degeneration. This is thought to occur mainly through apoptosis and epithelial-to-mesenchymal transition (EMT) of tubule epithelial cells, which give rise to a reduction of the tubular compartment and a scarring-like, fibrotic healing process of the interstitial compartment. In vivo blockade of TGF-β action has been shown to reduce CKD-associated tubular damage. However, a direct action of TGF-Β on tubule cells is controversial as the underlying mechanism. On the one hand, TGF-β is known to induce EMT of tubular cells, although its incidence in vivo can hardly explain the extent of the damage. On the other hand, a few publications have reported that TGF-Β induces a mild degree of apoptosis in cultured tubular cells. This most likely reflects the consequence of the cell-cycle arrest rather than a direct pro-apoptotic effect of TGF-β. The implications of these observations are analyzed in the pathological context, where normal tubular cells do not normally proliferate, but they might divide for repair purposes. Furthermore, renal fibrosis, a TGF-Β-mediated event, is integrated as a potential, indirect effect contributing to tubule deletion. © 2010 International Society of Nephrology.

Lopez-Novoa J.M.,University of Salamanca | Lopez-Novoa J.M.,Instituto Reina Sofia Of Investigacion Nefrologica | Quiros Y.,University of Salamanca | Quiros Y.,Instituto Reina Sofia Of Investigacion Nefrologica | And 7 more authors.
Kidney International | Year: 2011

Nephrotoxicity is one of the most important side effects and therapeutical limitations of aminoglycoside antibiotics, especially gentamicin. Despite rigorous patient monitoring, nephrotoxicity appears in 10-25% of therapeutic courses. Traditionally, aminoglycoside nephrotoxicity has been considered to result mainly from tubular damage. Both lethal and sub-lethal alterations in tubular cells handicap reabsorption and, in severe cases, may lead to a significant tubular obstruction. However, a reduced glomerular filtration is necessary to explain the symptoms of the disease. Reduced filtration is not solely the result of tubular obstruction and tubular malfunction, resulting in tubuloglomerular feedback activation; renal vasoconstriction and mesangial contraction are also crucial to fully explain aminoglycoside nephrotoxicity. This review critically presents an integrative view on the interactions of tubular, glomerular, and vascular effects of gentamicin, in the context of the most recent information available. Moreover, it discusses therapeutic perspectives for prevention of aminoglycoside nephrotoxicity derived from the pathophysiological knowledge. © 2011 International Society of Nephrology.

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