Suchergebnisse

Chronic kidney disease (CKD) is emerging as an important health problem due to the increase number of CKD patients and the absence of an effective curative treatment. Gremlin has been proposed as a novel therapeutic target for renal inflammatory diseases, acting via Vascular Endothelial Growth Factor Receptor-2 (VEGFR2). Although many evidences suggest that Gremlin could regulate renal fibrosis, the receptor involved has not been yet clarified. Gremlin, as other TGF-β superfamily members, regulates tubular epithelial to mesenchymal transition (EMT) and, therefore, could contribute to renal fibrosis. In cultured tubular epithelial cells Gremlin binding to VEGFR2 is linked to proinflammatory responses. Now, we have found out that in these cells VEGFR2 is also involved in the profibrotic actions of Gremlin. VEGFR2 blockade by a pharmacological kinase inhibitor or gene silencing diminished Gremlin-mediated gene upregulation of profibrotic factors and restored changes in EMT-related genes. Moreover, VEGFR2 inhibition blocked EMT phenotypic changes and dampened the rate of wound healing in response to Gremlin. The role of VEGFR2 in experimental fibrosis was evaluated in experimental unilateral ureteral obstruction. VEFGR2 inhibition diminished the upregulation of profibrotic genes and EMT changes, as well as the accumulation of extracellular matrix proteins, such as fibronectin and collagens in the obstructed kidneys. Notch pathway activation participates in renal damage progression by regulating cell growth/proliferation, regeneration and inflammation. In cultured tubular epithelial cells, Notch inhibition markedly downregulated Gremlin-induced EMT changes and wound healing speed. These results show that Gremlin regulates the EMT process via VEGFR2 and Notch pathway activation, suggesting that the Gremlin/VEGFR2 axis could be a potential therapeutic target for CKD. ; This work was supported by grants from the Instituto de Salud Carlos III (ISCIII) and Fondos FEDER European Union (PI16/02057, PI17/00119, PI17/01495, and Red de Investigación Renal REDINREN: RD16/0009), Sociedad Española de Nefrologia, "NOVELREN-CM: Enfermedad renal crónica: nuevas Estrategias para la prevención, Diagnóstico y tratamiento"; B2017/BMD-3751, B2017/BMD-3686 CIFRA2-CM, PAI 82140017, and FONDECYT 1160465 (Chile) and Bayer HealthCare AG (Grants4Targets initiative, Berlin, Germany).

La vía de Notch regula procesos importantes en el riñón implicados en el desarrollo embrionario y en situaciones de agresión tisular. Así, en una gran variedad de nefropatías crónicas humanas se ha descrito una activación local de este sistema, sugiriendo que algunos de sus componentes podrían ser biomarcadores de daño renal. Los estudios realizados en modelos experimentales, modulando genéticamente componentes de la vía Notch o mediante su bloqueo farmacológico con inhibidores de la γ-secretasa, han demostrado la participación de esta vía en la regeneración renal, en la apoptosis de podocitos, en la proliferación y activación de fibroblastos y en la transición epitelio-mesenquimal de las células tubuloepiteliales. Estudios recientes sugieren una interacción entre las vías Notch y NF-κB, la cual podría jugar un papel relevante en el proceso inflamatorio renal. Por otra parte, en los últimos años se han descrito miRNA que son capaces de regular componentes de la vía Notch y modular sus respuestas. Todos estos datos indican que el bloqueo de la vía de señalización Notch podría representar una nueva opción terapéutica para la enfermedad renal ; Notch pathway regulates key processes in the kidney, involved in embryonic development and tissue damage. In many human chronic renal diseases a local activation of Notch pathway has been described, suggesting that several components of Notch pathway could be considered as biomarkers of renal damage. Experimental studies by genetic modulation of Notch components or pharmacological approaches by γ-secretase inhibitors have demonstrated the role of this pathway in renal regeneration renal, podocyte apoptosis, proliferation and fibroblasts activation, and induction of epithelial to mesenchymal transition of tubular epithelial cells. Recent studies suggest an interaction between Notch and NF-κ B pathway involved in the regulation of renal inflammatory process. On the other hand, there are some miRNAs that could regulate Notch components and down-stream responses. All these data suggest that Notch blockade could be a novel therapeutic option for renal diseases ; Los estudios no publicados de este trabajo fueron financiados por la Sociedad Española de Nefrología, el Instituto de Salud Carlos III y Fondos FEDER European Union (ISCIII-RETIC RD16/0009, Redinren), y los proyectos de Chile: PAI 82140017 y FONDECYT 1160465

MicroRNAs (miRNAs) regulate gene expression posttranscriptionally and control biological processes (BPs), including fibrogenesis. Kidney fibrosis remains a clinical challenge and miRNAs may represent a valid therapeutic avenue. We show that miR‐9‐5p protected from renal fibrosis in the mouse model of unilateral ureteral obstruction (UUO). This was reflected in reduced expression of pro‐fibrotic markers, decreased number of infiltrating monocytes/macrophages, and diminished tubular epithelial cell injury and transforming growth factor‐beta 1 (TGF‐β1)‐dependent de‐differentiation in human kidney proximal tubular (HKC‐8) cells. RNA‐sequencing (RNA‐Seq) studies in the UUO model revealed that treatment with miR‐9‐5p prevented the downregulation of genes related to key metabolic pathways, including mitochondrial function, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and glycolysis. Studies in human tubular epithelial cells demonstrated that miR‐9‐5p impeded TGF‐β1‐induced bioenergetics derangement. The expression of the FAO‐related axis peroxisome proliferator‐activated receptor gamma coactivator 1 alpha (PGC‐1α)‐peroxisome proliferator‐activated receptor alpha (PPARα) was reduced by UUO, although preserved by the administration of miR‐9‐5p. We found that in mice null for the mitochondrial master regulator PGC‐1α, miR‐9‐5p was unable to promote a protective effect in the UUO model. We propose that miR‐9‐5p elicits a protective response to chronic kidney injury and renal fibrosis by inducing reprogramming of the metabolic derangement and mitochondrial dysfunction affecting tubular epithelial cells. ; This work was supported by Grants from the Ministerio de Economía y Competitividad (MINECO) SAF 2012‐31388 (SL) and SAF2015‐66107‐R (SL), both cofunded by the European Regional Development Fund, Instituto de Salud Carlos III REDinREN RD12/0021/0009 and RD16/0009/0016 (SL and MRO), PI17/00119 (MRO), SAF2015‐63904‐R (MM), cofunded by the European Regional Development Fund, European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska‐Curie grant agreement 721236‐TREATMENT (MM), Comunidad de Madrid "NOVELREN" B2017/BMD­3751 (SL and MRO), and Fundación Renal "Iñigo Alvarez de Toledo" (SL), all from Spain. The CBMSO receives institutional support from Fundación "Ramón Areces". VM and CNT were supported by predoctoral fellowships of the FPI Program (BES‐2013‐065986 and BES‐2014‐068929) from MINECO. ; Peer reviewed

Chronic kidney disease (CKD) remains a major epidemiological, clinical and biomedical challenge. During CKD, renal tubular epithelial cells (TECs) suffer a persistent inflammatory and profibrotic response. Fatty acid oxidation (FAO), the main source of energy for TECs, is reduced in kidney fibrosis and contributes to its pathogenesis. To determine if FAO gain-offunction (FAO-GOF) could protect from fibrosis, we generated a conditional transgenic mouse model with overexpression of the fatty acid shuttling enzyme carnitine palmitoyltransferase 1 A (CPT1A) in TECs. Cpt1a knock-in (CPT1A KI) mice subjected to three different models of renal fibrosis (unilateral ureteral obstruction, folic acid nephropathy-FAN and adenine induced nephrotoxicity) exhibited decreased expression of fibrotic markers, a blunted pro-inflammatory response and reduced epithelial cell damage and macrophage influx. Protection from fibrosis was also observed when Cpt1a overexpression was induced after FAN. FAO-GOF restituted oxidative metabolism and mitochondrial number and enhanced bioenergetics increasing palmitate oxidation and ATP levels, changes also recapitulated in TECs exposed to profibrotic stimuli. Studies in patients evidenced decreased CPT1 levels and increased accumulation of short and middle chain acylcarnitines, reflecting impaired FAO in human CKD. We propose that strategies based on FAO-GOF may constitute powerful alternatives to combat fibrosis inherent to CKD ; Ministerio de Economia y Competitividad (MINECO) SAF2012-31388 (SL), SAF2015-66107-R (SL), PID2019-104233RB-100 (SL), PI17/01513 (DRP), SAF2017-83813-C3-1-R (DS and LH), cofunded by the European Regional Development Fund, Instituto de Salud Carlos III REDinREN RD12/0021/0009 and RD16/0009/0016 (SL, DRP, and MRO), PI17/00119 (MRO), FIS PI17/00625 (DRP), Comunidad de Madrid "NOVELREN" B2017/BMD-3751 (SL, DRP, and MRO)"; Spanish Society of Nephrology (Fundacion Senefro 2017) (SL) and Fundacion Renal "Iñigo Alvarez de Toledo" (SL), the Centro de Investigacion Biomedica en Red de Fisiopatologia de la Obesidad y la Nutricion (CIBEROBN) CB06/03/0001 (DS), the Government of Catalonia 2017SGR278 (DS), and the Fundacio La Marato de TV3 201627-30 (DS), all from Spain. The CBMSO receives institutional support from Fundacion "Ramon Areces."