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Ortiz A.,Nephrology | Ortiz A.,Autonomous University of Madrid | Sanchez-Nino M.D.,Nephrology | Izquierdo M.C.,Nephrology | And 17 more authors.
European Journal of Pharmacology | Year: 2015

Abstract Acute kidney injury (AKI) and chronic kidney disease (CKD) are associated with decreased renal function and increased mortality risk, while the therapeutic armamentarium is unsatisfactory. The availability of adequate animal models may speed up the discovery of biomarkers for disease staging and therapy individualization as well as design and testing of novel therapeutic strategies. Some longstanding animal models have failed to result in therapeutic advances in the clinical setting, such as kidney ischemia-reperfusion injury and diabetic nephropathy models. In this regard, most models for diabetic nephropathy are unsatisfactory in that they do not evolve to renal failure. Satisfactory models for additional nephropathies are needed. These include anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, IgA nephropathy, anti-phospholipase-A2-receptor (PLA2R) membranous nephropathy and Fabry nephropathy. However, recent novel models hold promise for clinical translation. Thus, the AKI to CKD translation has been modeled, in some cases with toxins of interest for human CKD such as aristolochic acid. Genetically modified mice provide models for Alport syndrome evolving to renal failure that have resulted in clinical recommendations, polycystic kidney disease models that have provided clues for the development of tolvaptan, that was recently approved for the human disease in Japan; and animal models also contributed to target C5 with eculizumab in hemolytic uremic syndrome. Some ongoing trials explore novel concepts derived from models, such TWEAK targeting as tissue protection for lupus nephritis. We now review animal models reproducing diverse, genetic and acquired, causes of AKI and CKD evolving to kidney failure and discuss the contribution to clinical translation and prospects for the future. © 2015 Elsevier B.V.


Nastou D.,Red Cross | Sanchez-Nino M.D.,REDINREN | Ortiz A.,Autonomous University of Madrid
Drugs | Year: 2014

Phosphate excess is associated with increased mortality in patients with chronic kidney disease (CKD) and has recently been linked to accelerated aging. Oral phosphate binders are prescribed to patients with CKD to prevent absorption of dietary phosphate. Currently available binders have been associated with impaired outcomes (calcium-based binders) or are expensive (non-calcium-based binders). Iron-based phosphate binders represent a new class of phosphate binders. Four iron-based phosphate binders have undergone testing in clinical trials. The development of fermagate and SBR759 is currently on hold due to suboptimal and adverse effect profiles in at least some clinical trials. Ferric citrate and sucroferric oxyhydroxide (PA21) are at different stages of application for regulatory approval after being found safe and efficacious in decreasing serum phosphate. Iron from ferric citrate is more readily absorbed than that from sucroferric oxyhydroxide. Sucroferric oxyhydroxide was launched in the USA in 2014 for the treatment of hyperphosphatemia in adult dialysis patients. Ferric citrate may be more suited for chronic treatment of hyperphosphatemia in CKD patients requiring iron supplements but its use may have to be limited in time because of potential for iron overload in patients not needing iron or not receiving erythropoiesis-stimulating agents. In contrast, sucroferric oxyhydroxide may be more suited for hyperphosphatemic CKD patients not requiring iron supplements. © 2014 Springer International Publishing Switzerland.


Husi H.,University of Glasgow | Sanchez-Nino M.D.,Institute Investigacion Sanitaria IDIPAZ | Delles C.,University of Glasgow | Mullen W.,University of Glasgow | And 5 more authors.
BMC Systems Biology | Year: 2013

Background: Acute kidney injury (AKI) is a frequent condition in hospitalised patients undergoing major surgery or the critically ill and is associated with increased mortality. Based on the volume of the published literature addressing this condition, reporting both supporting as well as conflicting molecular evidence, it is apparent that a comprehensive analysis strategy is required to understand and fully delineate molecular events and pathways which can be used to describe disease induction and progression as well as lead to a more targeted approach in intervention therapies.Results: We used a Systems Biology approach coupled with a de-novo high-resolution proteomic analysis of kidney cortex samples from a mouse model of folic acid-induced AKI (12 animals in total) and show comprehensive mapping of signalling cascades, gene activation events and metabolite interference by mapping high-resolution proteomic datasets onto a de-novo hypothesis-free dataspace. The findings support the involvement of the glutamatergic signalling system in AKI, induced by over-activation of the N-methyl-D-aspartate (NMDA)-receptor leading to apoptosis and necrosis by Ca2+-influx, calpain and caspase activation, and co-occurring reactive oxygen species (ROS) production to DNA fragmentation and NAD-rundown. The specific over-activation of the NMDA receptor may be triggered by the p53-induced protein kinase Dapk1, which is a known non-reversible cell death inducer in a neurological context. The pathway mapping is consistent with the involvement of the Renin-Angiotensin Aldosterone System (RAAS), corticoid and TNFα signalling, leading to ROS production and gene activation through NFκB, PPARγ, SMAD and HIF1α trans-activation, as well as p53 signalling cascade activation. Key elements of the RAAS-glutamatergic axis were assembled as a novel hypothetical pathway and validated by immunohistochemistry.Conclusions: This study shows to our knowledge for the first time in a molecular signal transduction pathway map how AKI is induced, progresses through specific signalling cascades that may lead to end-effects such as apoptosis and necrosis by uncoupling of the NMDA receptor. Our results can potentially pave the way for a targeted pharmacological intervention in disease progression or induction. © 2013 Husi et al.; licensee BioMed Central Ltd.


Sanz A.B.,Dialysis Unit | Izquierdo M.C.,Dialysis Unit | Sanchez-Nino M.D.,REDinREN | Ucero A.C.,Dialysis Unit | And 8 more authors.
Nephrology Dialysis Transplantation | Year: 2014

Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) activates the fibroblast growth factor-inducible-14 (Fn14) receptor. TWEAK has actions on intrinsic kidney cells and on inflammatory cells of potential pathophysiological relevance. The effects of TWEAK in tubular cells have been explored in most detail. In cultured murine tubular cells TWEAK induces the expression of inflammatory cytokines, downregulates the expression of Klotho, is mitogenic, and in the presence of sensitizing agents promotes apoptosis. Similar actions were observed on glomerular mesangial cells. In vivo TWEAK actions on healthy kidneys mimic cell culture observations.Increased expression of TWEAK and Fn14 was reported in human and experimental acute and chronic kidney injury. The role of TWEAK/Fn14 in kidney injury has been demonstrated in non-inflammatory compensatory renal growth, acute kidney injury and chronic kidney disease of immune and non-immune origin, including hyperlipidaemic nephropathy, lupus nephritis (LN) and anti-GBM nephritis. The nephroprotective effect of TWEAK or Fn14 targeting in immune-mediated kidney injury is the result of protection from TWEAK-induced injury of renal intrinsic cells, not from interference with the immune response.A phase I dose-ranging clinical trial demonstrated the safety of anti-TWEAK antibodies in humans. A phase II randomized placebo-controlled clinical trial exploring the efficacy, safety and tolerability of neutralizing anti-TWEAK antibodies as a tissue protection strategy in LN is ongoing. The eventual success of this trial may expand the range of kidney diseases in which TWEAK targeting should be explored. © The Author 2014.


Henaut L.,Autonomous University of Madrid | Sanchez-Nino M.D.,Autonomous University of Madrid | Aldamiz-Echevarria Castillo G.,Autonomous University of Madrid | Sanz A.B.,Autonomous University of Madrid | And 2 more authors.
Expert Opinion on Therapeutic Targets | Year: 2016

Introduction: Cardiac valve calcification and vascular calcification (VC) are associated with cardiovascular mortality in the general population and in patients with chronic kidney disease (CKD). CKD, diabetes mellitus, and atherosclerosis are among the causes of systemic inflammation that are associated with VC.Areas covered: This review collates clinical and experimental evidence that inflammation accelerates VC progression. Specifically, we review the actions of key pro-inflammatory cytokines and inflammation-related transcription factors on VC, and the role played by senescence. Inflammatory cytokines, such as the TNF superfamily and IL-6 superfamily, and inflammation-related transcription factor NF-B promote calcification in cultured vascular smooth muscle cells, valvular interstitial cells, or experimental animal models through direct effects, but also indirectly by decreasing circulating Fetuin A or Klotho levels.Expert opinion: Experimental evidence suggests a causal link between inflammation and VC that would change the clinical approach to prevention and treatment of VC. However, the molecular basis remains unclear and little is known about VC in humans treated with drugs targeting inflammatory cytokines. The effect of biologicals targeting TNF-, RANKL, IL-6, and other inflammatory mediators on VC, in addition to the impact of dietary phosphate in patients with chronic systemic inflammation, requires study. © 2015 Taylor & Francis.


PubMed | REDinREN, University of Huelva, University of Cordoba, Spain and Laboratory of Nephrology
Type: Journal Article | Journal: European journal of clinical investigation | Year: 2015

Vascular calcification (VC) is highly prevalent in patients with chronic kidney disease (CKD). Low magnesium levels are associated with VC, and recent invitro studies confirm a protective role of magnesium, which is mediated by its entry into the VSMCs through the Transient Receptor Potential Melastatin 7 (TRPM7) channel. The role of Angiotensin II (Ang II) on VC is still unclear. As Ang II is able to stimulate TRPM7 activity, we hypothesize that it might prevent VC. Thus, the aim of this study was to dissect the direct effect of Ang II on VC.We worked with a model of high phosphate (HP)-induced calcification in human aortic smooth muscle cells, which resembles the CKD-related VC.Addition of Ang II to cells growing in HP decreased calcification, which was associated with the upregulation of the osteogenic factors BMP2, Runx2/Cbfa1, Osterix and ALP. A reduction of magnesium entry into the HP-calcifying cells was found. The treatment with Ang II avoided this reduction, which was reversed by the cotreatment with the TRPM7-inhibitor 2-APB. The protective effect of Ang II was related to AT1R-induced ERK1/2 MAPKinase activation. HP-induced calcification was also associated with the upregulation of the canonical Wnt/beta-catenin pathway, while its downregulation was related to attenuation of calcification by AngII.As hypothesized, Ang II prevented phosphate-induced calcification in VSMCs, which appears mediated by the increase of magnesium influx and by the activation of the ERK1/2 and the inhibition of the canonical Wnt/beta-catenin signalling pathways.


Tabara L.C.,IIS Fundacion Jimenez Diaz | Poveda J.,IIS Fundacion Jimenez Diaz | Martin-Cleary C.,IIS Fundacion Jimenez Diaz | Selgas R.,REDINREN | And 2 more authors.
Expert reviews in molecular medicine | Year: 2014

Acute kidney injury (AKI) is a serious clinical condition with no effective treatment. Tubular cells are key targets in AKI. Tubular cells and, specifically, proximal tubular cells are extremely rich in mitochondria and mitochondrial changes had long been known to be a feature of AKI. However, only recent advances in understanding the molecules involved in mitochondria biogenesis and dynamics and the availability of mitochondria-targeted drugs has allowed the exploration of the specific role of mitochondria in AKI. We now review the morphological and functional mitochondrial changes during AKI, as well as changes in the expression of mitochondrial genes and proteins. Finally, we summarise the current status of novel therapeutic strategies specifically targeting mitochondria such as mitochondrial permeability transition pore (MPTP) opening inhibitors (cyclosporine A (CsA)), quinone analogues (MitoQ, SkQ1 and SkQR1), superoxide dismutase (SOD) mimetics (Mito-CP), Szeto-Schiller (SS) peptides (Bendavia) and mitochondrial division inhibitors (mdivi-1). MitoQ, SkQ1, SkQR1, Mito-CP, Bendavia and mdivi-1 have improved the course of diverse experimental models of AKI. Evidence for a beneficial effect of CsA on human cardiac ischaemia-reperfusion injury derives from a clinical trial; however, CsA is nephrotoxic. MitoQ and Bendavia have been shown to be safe for humans. Ongoing clinical trials are testing the efficacy of Bendavia in AKI prevention following renal artery percutaneous transluminal angioplasty.


PubMed | REDINREN and IIS Fundacion Jimenez Diaz
Type: | Journal: Expert reviews in molecular medicine | Year: 2014

Acute kidney injury (AKI) is a serious clinical condition with no effective treatment. Tubular cells are key targets in AKI. Tubular cells and, specifically, proximal tubular cells are extremely rich in mitochondria and mitochondrial changes had long been known to be a feature of AKI. However, only recent advances in understanding the molecules involved in mitochondria biogenesis and dynamics and the availability of mitochondria-targeted drugs has allowed the exploration of the specific role of mitochondria in AKI. We now review the morphological and functional mitochondrial changes during AKI, as well as changes in the expression of mitochondrial genes and proteins. Finally, we summarise the current status of novel therapeutic strategies specifically targeting mitochondria such as mitochondrial permeability transition pore (MPTP) opening inhibitors (cyclosporine A (CsA)), quinone analogues (MitoQ, SkQ1 and SkQR1), superoxide dismutase (SOD) mimetics (Mito-CP), Szeto-Schiller (SS) peptides (Bendavia) and mitochondrial division inhibitors (mdivi-1). MitoQ, SkQ1, SkQR1, Mito-CP, Bendavia and mdivi-1 have improved the course of diverse experimental models of AKI. Evidence for a beneficial effect of CsA on human cardiac ischaemia-reperfusion injury derives from a clinical trial; however, CsA is nephrotoxic. MitoQ and Bendavia have been shown to be safe for humans. Ongoing clinical trials are testing the efficacy of Bendavia in AKI prevention following renal artery percutaneous transluminal angioplasty.


PubMed | REDINREN and Metropolitan Autonomous University
Type: Journal Article | Journal: Journal of clinical medicine | Year: 2015

Diabetic kidney disease is the most frequent cause of end-stage renal disease. This implies failure of current therapeutic approaches based on renin-angiotensin system (RAS) blockade. Recent phase 3 clinical trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced diabetic kidney disease failed to meet the primary endpoint or terminated on safety concerns, respectively. However, various novel strategies are undergoing phase 2 and 3 randomized controlled trials targeting inflammation, fibrosis and signaling pathways. Among agents currently undergoing trials that may modify the clinical practice on top of RAS blockade in a 5-year horizon, anti-inflammatory agents currently hold the most promise while anti-fibrotic agents have so far disappointed. Pentoxifylline, an anti-inflammatory agent already in clinical use, was recently reported to delay estimated glomerular filtration rate (eGFR) loss in chronic kidney disease (CKD) stage 3-4 diabetic kidney disease when associated with RAS blockade and promising phase 2 data are available for the pentoxifylline derivative CTP-499. Among agents targeting chemokines or chemokine receptors, the oral small molecule C-C chemokine receptor type 2 (CCR2) inhibitor CCX140 decreased albuminuria and eGFR loss in phase 2 trials. A dose-finding trial of the anti-IL-1 antibody gevokizumab in diabetic kidney disease will start in 2015. However, clinical development is most advanced for the endothelin receptor A blocker atrasentan, which is undergoing a phase 3 trial with a primary outcome of preserving eGFR. The potential for success of these approaches and other pipeline agents is discussed in detail.


PubMed | Research Center Principe Felipe, REDINREN and Laboratory of Nephrology and Vascular Pathology
Type: | Journal: Archives of toxicology | Year: 2016

Cyclosporine A (CsA) successfully prevents allograft rejection, but nephrotoxicity is still a dose-limiting adverse effect. TLR4 activation promotes kidney damage but whether this innate immunity receptor mediates CsA nephrotoxicity is unknown. The in vivo role of TLR4 during CsA nephrotoxicity was studied in mice co-treated with CsA and the TLR4 inhibitor TAK242 and also in TLR4

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