Long Non-Coding RNA Signatures in the Ileum and Colon of Crohn's Disease Patients and Effect of Anti-TNF-α Treatment on Their Modulation.

Biological therapies only benefit one-third of patients with Crohn's disease (CD). For this reason, a deeper understanding of the mechanisms by which biologics elicit their effect on intestinal mucosa is needed. Increasing evidence points toward the involvement of long noncoding RNAs (lncRNAs) in the pathogenesis of CD, although their role remains poorly studied. We aimed to characterize lncRNA profiles in the ileum and colon from CD patients and evaluate the effect of anti-TNF-α treatment on their transcription. Terminal ileum and left colon samples from 30 patients (active CD = 10, quiescent CD = 10, and healthy controls (HCs) = 10) were collected for RNA-seq. The patients were classified according to endoscopic activity. Furthermore, biopsies were cultured with infliximab, and their transcriptome was determined by Illumina gene expression array. A total of 678 differentially expressed lncRNAs between the terminal ileum and left colon were identified in HCs, 438 in patients with quiescent CD, and 468 in patients with active CD. Additionally, we identified three new lncRNAs in the ileum associated with CD activity. No differences were observed when comparing the effect of infliximab according to intestinal location, presence of disease (CD vs. HC), and activity (active vs. quiescent). The expression profiles of lncRNAs are associated with the location of intestinal tissue, being very different in the ileum and colon. The presence of CD and disease activity are associated with the differential expression of lncRNAs. No modulatory effect of infliximab has been observed in the lncRNA transcriptome.

Effects of Golimumab and Ustekinumab on Circulating Dendritic Cell Migratory Capacity in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic condition which includes ulcerative colitis (UC) and Crohn's disease (CD), the origins of which are not yet fully understood. Both conditions involve an exacerbated immune response in the intestinal tract, leading to tissue inflammation. Dendritic cells (DCs) are antigen-presenting cells crucial for maintaining tolerance in the gastrointestinal mucosa. Previous research has indicated that DC recruitment to the intestinal mucosa is more pronounced in individuals with IBD, but the specific mechanisms governing this migration remain unclear. This study aimed to assess the expression of various homing markers and the migratory abilities of circulating DC subsets in response to intestinal chemotactic signals. Additionally, this study examined how golimumab and ustekinumab impact these characteristics in individuals with IBD compared to healthy controls. The findings revealed that a particular subset of DCs known as type 2 conventional DCs (cDC2) displayed a more pronounced migratory profile compared to other DC subsets. Furthermore, the study observed that golimumab and ustekinumab had varying effects on the migratory profile of cDC1 in individuals with CD and UC. While CCL2 did not exert a chemoattractant effect on DC subsets in this patient cohort, treatment with golimumab and ustekinumab enhanced their migratory capacity towards CCL2 and CCL25 while reducing their migration towards MadCam1. In conclusion, this study highlights that cDC2 exhibits a heightened migratory profile towards the gastrointestinal mucosa compared to other DC subsets. This finding could be explored further for the development of new diagnostic biomarkers or the identification of potential immunomodulatory targets in the context of IBD.

The Synthetic Flavonoid Hidrosmin Improves Endothelial Dysfunction and Atherosclerotic Lesions in Diabetic Mice.

In diabetes, chronic hyperglycemia, dyslipidemia, inflammation and oxidative stress contribute to the progression of macro/microvascular complications. Recently, benefits of the use of flavonoids in these conditions have been established. This study investigates, in two different mouse models of diabetes, the vasculoprotective effects of the synthetic flavonoid hidrosmin on endothelial dysfunction and atherogenesis. In a type 2 diabetes model of leptin-receptor-deficient (db/db) mice, orally administered hidrosmin (600 mg/kg/day) for 16 weeks markedly improved vascular function in aorta and mesenteric arteries without affecting vascular structural properties, as assessed by wire and pressure myography. In streptozotocin-induced type 1 diabetic apolipoprotein E-deficient mice, hidrosmin treatment for 7 weeks reduced atherosclerotic plaque size and lipid content; increased markers of plaque stability; and decreased markers of inflammation, senescence and oxidative stress in aorta. Hidrosmin showed cardiovascular safety, as neither functional nor structural abnormalities were noted in diabetic hearts. Ex vivo, hidrosmin induced vascular relaxation that was blocked by nitric oxide synthase (NOS) inhibition. In vitro, hidrosmin stimulated endothelial NOS activity and NO production and downregulated hyperglycemia-induced inflammatory and oxidant genes in vascular smooth muscle cells. Our results highlight hidrosmin as a potential add-on therapy in the treatment of macrovascular complications of diabetes.

Meta-Inflammation and De Novo Lipogenesis Markers Are Involved in Metabolic Associated Fatty Liver Disease Progression in BTBR ob/ob Mice.

Metabolic associated fatty liver disease (MAFLD) is a hepatic manifestation of metabolic syndrome and usually associated with obesity and diabetes. Our aim is to characterize the pathophysiological mechanism involved in MAFLD development in Black Tan and brachyuric (BTBR) insulin-resistant mice in combination with leptin deficiency (ob/ob). We studied liver morphology and biochemistry on our diabetic and obese mice model (BTBR ob/ob) as well as a diabetic non-obese control (BTBR + streptozotocin) and non-diabetic control mice (BTBR wild type) from 4-22 weeks. Lipid composition was assessed, and lipid related pathways were studied at transcriptional and protein level. Microvesicular steatosis was evident in BTBR ob/ob from week 6, progressing to macrovesicular in the following weeks. At 12th week, inflammatory clusters, activation of STAT3 and Nrf2 signaling pathways, and hepatocellular ballooning. At 22 weeks, the histopathological features previously observed were maintained and no signs of fibrosis were detected. Lipidomic analysis showed profiles associated with de novo lipogenesis (DNL). BTBR ob/ob mice develop MAFLD profile that resemble pathological features observed in humans, with overactivation of inflammatory response, oxidative stress and DNL signaling pathways. Therefore, BTBR ob/ob mouse is an excellent model for the study of the steatosis to steatohepatitis transition.

CCN2 (Cellular Communication Network Factor 2) Deletion Alters Vascular Integrity and Function Predisposing to Aneurysm Formation.

BACKGROUND: CCN2 (cellular communication network factor 2) is a matricellular protein involved in cell communication and microenvironmental signaling responses. CCN2 is known to be overexpressed in several cardiovascular diseases, but its role is not completely understood. METHODS: Here, CCN2 involvement in aortic wall homeostasis and response to vascular injury was investigated in inducible <i>Ccn2</i>-deficient mice, with induction of vascular damage by infusion of Ang II (angiotensin II; 15 days), which is known to upregulate CCN2 expression in the aorta. RESULTS: Ang II infusion in CCN2-silenced mice lead to 60% mortality within 10 days due to rapid development and rupture of aortic aneurysms, as evidenced by magnetic resonance imaging, echography, and histological examination. <i>Ccn2</i> deletion decreased systolic blood pressure and caused aortic structural and functional changes, including elastin layer disruption, smooth muscle cell alterations, augmented distensibility, and increased metalloproteinase activity, which were aggravated by Ang II administration. Gene ontology analysis of RNA sequencing data identified aldosterone biosynthesis as one of the most enriched terms in CCN2-deficient aortas. Consistently, treatment with the mineralocorticoid receptor antagonist spironolactone before and during Ang II infusion reduced aneurysm formation and mortality, underscoring the importance of the aldosterone pathway in Ang II-induced aorta pathology. CONCLUSIONS: CCN2 is critically involved in the functional and structural homeostasis of the aorta and in maintenance of its integrity under Ang II-induced stress, at least, in part, by disruption of the aldosterone pathway. Thus, this study opens new avenues to future studies in disorders associated to vascular pathologies.

Nephroprotective Effects of Synthetic Flavonoid Hidrosmin in Experimental Diabetic Nephropathy.

Diabetes mellitus (DM) is a high-impact disease commonly characterized by hyperglycemia, inflammation, and oxidative stress. Diabetic nephropathy (DN) is a common diabetic microvascular complication and the leading cause of chronic kidney disease worldwide. This study investigates the protective effects of the synthetic flavonoid hidrosmin (5-O-(beta-hydroxyethyl) diosmin) in experimental DN induced by streptozotocin injection in apolipoprotein E deficient mice. Oral administration of hidrosmin (300 mg/kg/day, n = 11) to diabetic mice for 7 weeks markedly reduced albuminuria (albumin-to-creatinine ratio: 47 ± 11% vs. control) and ameliorated renal pathological damage and expression of kidney injury markers. Kidneys of hidrosmin-treated mice exhibited lower content of macrophages and T cells, reduced expression of cytokines and chemokines, and attenuated inflammatory signaling pathways. Hidrosmin treatment improved the redox balance by reducing prooxidant enzymes and enhancing antioxidant genes, and also decreased senescence markers in diabetic kidneys. In vitro, hidrosmin dose-dependently reduced the expression of inflammatory and oxidative genes in tubuloepithelial cells exposed to either high-glucose or cytokines, with no evidence of cytotoxicity at effective concentrations. In conclusion, the synthetic flavonoid hidrosmin exerts a beneficial effect against DN by reducing inflammation, oxidative stress, and senescence pathways. Hidrosmin could have a potential role as a coadjutant therapy for the chronic complications of DM.

Role of Macrophages and Related Cytokines in Kidney Disease.

Inflammation is a key characteristic of kidney disease, but this immune response is two-faced. In the acute phase of kidney injury, there is an activation of the immune cells to fight against the insult, contributing to kidney repair and regeneration. However, in chronic kidney diseases (CKD), immune cells that infiltrate the kidney play a deleterious role, actively participating in disease progression, and contributing to nephron loss and fibrosis. Importantly, CKD is a chronic inflammatory disease. In early CKD stages, patients present sub-clinical inflammation, activation of immune circulating cells and therefore, anti-inflammatory strategies have been proposed as a common therapeutic target for renal diseases. Recent studies have highlighted the plasticity of immune cells and the complexity of their functions. Among immune cells, monocytes/macrophages play an important role in all steps of kidney injury. However, the phenotype characterization between human and mice immune cells showed different markers; therefore the extrapolation of experimental studies in mice could not reflect human renal diseases. Here we will review the current information about the characteristics of different macrophage phenotypes, mainly focused on macrophage-related cytokines, with special attention to the chemokine CCL18, and its murine functional homolog CCL8, and the macrophage marker CD163, and their role in kidney pathology.

[Interleukin-17A: Possible mediator and therapeutic target in hypertension]. / Interleuquina-17A: posible mediador y diana terapéutica en la hipertensión.

Interleukin-17A (IL-17A) is a proinflammatory cytokine produced by cells of the immune system, predominantly Th17 lymphocytes and γδ lymphocytes. In this paper, we review the role of IL-17A in the pathogenesis of hypertension and target organ damage. Studies in mice have shown that IL-17A increases blood pressure, probably by acting on multiple levels. Furthermore, IL-17A plasma concentrations are already elevated in patients with mild or moderate hypertension. Preclinical studies on arterial hypertension have detected IL-17A-producing cells in target organs such as the heart, vessels and kidneys. Patients with hypertensive nephrosclerosis show kidney infiltration by Th17 lymphocytes and γδ lymphocytes that express IL-17A. In addition, in experimental models of hypertension, blocking IL-17A by genetic strategies, or using neutralising antibodies, lowers blood pressure by acting on the vascular wall and tubule sodium transport and reduces damage to target organs. As a whole, the data presented in this review suggest that IL-17A participates in the regulation of blood pressure and in the genesis and maintenance of arterial hypertension, and may constitute a therapeutic target in the future.

CCN2 Increases TGF-ß Receptor Type II Expression in Vascular Smooth Muscle Cells: Essential Role of CCN2 in the TGF-ß Pathway Regulation.

The cellular communication network factor 2 (CCN2/CTGF) has been traditionally described as a mediator of the fibrotic responses induced by other factors including the transforming growth factor ß (TGF-ß). However, several studies have defined a direct role of CCN2 acting as a growth factor inducing oxidative and proinflammatory responses. The presence of CCN2 and TGF-ß together in the cellular context has been described as a requisite to induce a persistent fibrotic response, but the precise mechanisms implicated in this relation are not described yet. Considering the main role of TGF-ß receptors (TßR) in the TGF-ß pathway activation, our aim was to investigate the effects of CCN2 in the regulation of TßRI and TßRII levels in vascular smooth muscle cells (VSMCs). While no differences were observed in TßRI levels, an increase in TßRII expression at both gene and protein level were found 48 h after stimulation with the C-terminal fragment of CCN2 (CCN2(IV)). Cell pretreatment with a TßRI inhibitor did not modify TßRII increment induced by CCN2(VI), demonstrating a TGF-ß-independent response. Secondly, CCN2(IV) rapidly activated the SMAD pathway in VSMCs, this being crucial in the upregulation of TßRII since the preincubation with an SMAD3 inhibitor prevented it. Similarly, pretreatment with the epidermal growth factor receptor (EGFR) inhibitor erlotinib abolished TßRII upregulation, indicating the participation of this receptor in the observed responses. Our findings suggest a direct role of CCN2 maintaining the TGF-ß pathway activation by increasing TßRII expression in an EGFR-SMAD dependent manner activation.

Interleukin-17A: Potential mediator and therapeutic target in hypertension.

Interleukin-17A (IL-17A) is a proinflammatory cytokine produced by cells of the immune system, predominantly Th17 and γδ lymphocytes. In this paper, we review the role of IL-17A in the pathogenesis of hypertension and in target organ damage. Preclinical studies in mice have shown that systemic adminstration of IL-17A increases blood pressure, probably by acting on multiple levels. Furthermore, IL-17A plasma concentrations are already elevated in patients with mild or moderate hypertension. Many studies in hypertensive mice models have detected IL-17A-producing cells in target organs such as the heart, vessels and kidneys. Patients with hypertensive nephrosclerosis show kidney infiltration by Th17 lymphocytes and γδ lymphocytes that express IL-17A. In addition, in experimental models of hypertension, the blockade of IL-17A by genetic strategies or using neutralizing antibodies, disminished blood pressure, probablyby acting on the small mesenteric arteries as well as in the regulation of tubule sodium transport. Moreover, IL-17A inhibition reduces end-organs damage. As a whole, the data presented in this review suggest that IL-17A participates in the regulation of blood pressure and in the genesis and maintenance of arterial hypertension, and may constitute a therapeutic target of hypertension-related pathologies in the future.

Deletion of delta-like 1 homologue accelerates renal inflammation by modulating the Th17 immune response.

Preclinical studies have demonstrated that activation of the NOTCH pathway plays a key role in the pathogenesis of kidney damage. There is currently no information on the role of the Delta-like homologue 1 (DLK1), a NOTCH inhibitor, in the regulation of renal damage. Here, we investigated the contribution of DLK1 to experimental renal damage and the underlying molecular mechanisms. Using a Dlk1-null mouse model in the experimental renal damage of unilateral ureteral obstruction, we found activation of NOTCH, as shown by increased nuclear translocation of the NOTCH1 intracellular domain, and upregulation of Dlk2/hey-1 expression compared to wild-type (WT) littermates. NOTCH1 over-activation in Dlk1-null injured kidneys was associated with a higher inflammatory response, characterized by infiltration of inflammatory cells, mainly CD4/IL17A + lymphocytes, and activation of the Th17 immune response. Furthermore, pharmacological NOTCH blockade inhibited the transcription factors controlling Th17 differentiation and gene expression of the Th17 effector cytokine IL-17A and other related-inflammatory factors, linked to a diminution of inflammation in the injured kidneys. We propose that the non-canonical NOTCH ligand DLK1 acts as a NOTCH antagonist in renal injury regulating the Th17-mediated inflammatory response.

Interleukin-17A induces vascular remodeling of small arteries and blood pressure elevation.

An important link exists between hypertension and inflammation. Hypertensive patients present elevated circulating levels of proinflammatory cytokines, including interleukin-17A (IL-17A). This cytokine participates in host defense, autoimmune and chronic inflammatory pathologies, and cardiovascular diseases, mainly through the regulation of proinflammatory factors. Emerging evidence also suggests that IL-17A could play a role in regulating blood pressure and end-organ damage. Here, our preclinical studies in a murine model of systemic IL-17A administration showed that increased levels of circulating IL-17A raised blood pressure induced inward remodeling of small mesenteric arteries (SMAs) and arterial stiffness. In IL-17A-infused mice, treatment with hydralazine and hydrochlorothiazide diminished blood pressure elevation, without modifying mechanical and structural properties of SMA, suggesting a direct vascular effect of IL-17A. The mechanisms of IL-17A seem to involve an induction of vascular smooth muscle cell (VSMC) hypertrophy and phenotype changes, in the absence of extracellular matrix (ECM) proteins accumulation. Accordingly, treatment with an IL-17A neutralizing antibody diminished SMA remodeling in a model of angiotensin II (Ang II) infusion. Moreover, in vitro studies in VSMCs reported here, provide further evidence of the direct effects of IL-17A on cell growth responses. Our experimental data suggest that IL-17A is a key mediator of vascular remodeling of the small arteries, which might contribute, at least in part, to blood pressure elevation.

Molecular Regulation of Notch Signaling by Gremlin.

Gremlin is a member of the TGF-ß superfamily that can act as a BMP antagonist, and recently, has been described as a ligand of the vascular endothelial growth factor receptor 2 (VEGFR2). Gremlin shares properties with the Notch signaling pathway. Both participate in embryonic development and are reactivated in pathological conditions. Gremlin is emerging as a potential therapeutic target and biomarker of renal diseases. Here we review the role of the Gremlin-VEGFR2 axis in renal damage and downstream signaling mechanisms, such as Notch pathway.

Could IL-17A Be a Novel Therapeutic Target in Diabetic Nephropathy?

Chronic kidney disease has become a major medical issue in recent years due to its high prevalence worldwide, its association with premature mortality, and its social and economic implications. A number of patients gradually progress to end-stage renal disease (ESRD), requiring then dialysis and kidney transplantation. Currently, approximately 40% of patients with diabetes develop kidney disease, making it the most prevalent cause of ESRD. Thus, more effective therapies for diabetic nephropathy are needed. In preclinical studies of diabetes, anti-inflammatory therapeutic strategies have been used to protect the kidneys. Recent evidence supports that immune cells play an active role in the pathogenesis of diabetic nephropathy. Th17 immune cells and their effector cytokine IL-17A have recently emerged as promising targets in several clinical conditions, including renal diseases. Here, we review current knowledge regarding the involvement of Th17/IL-17A in the genesis of diabetic renal injury, as well as the rationale behind targeting IL-17A as an additional therapy in patients with diabetic nephropathy.

Interleukin 17A Participates in Renal Inflammation Associated to Experimental and Human Hypertension.

Hypertension is now considered as an inflammatory disease, and the kidney is a key end-organ target. Experimental and clinical studies suggest that interleukin 17A (IL-17A) is a promising therapeutic target in immune and chronic inflammatory diseases, including hypertension and kidney disease. Elevated circulating IL-17A levels have been observed in hypertensive patients. Our aim was to investigate whether chronically elevated circulating IL-17A levels could contribute to kidney damage, using a murine model of systemic IL-17A administration. Blood pressure increased after 14 days of IL-17A infusion in mice when compared with that in control mice, and this was associated to kidney infiltration by inflammatory cells, including CD3+ and CD4+ lymphocytes and neutrophils. Moreover, proinflammatory factors and inflammatory-related intracellular mechanisms were upregulated in kidneys from IL-17A-infused mice. In line with these findings, in the model of angiotensin II infusion in mice, IL-17A blockade, using an anti-IL17A neutralizing antibody, reduced kidney inflammatory cell infiltrates and chemokine overexpression. In kidney biopsies from patients with hypertensive nephrosclerosis, IL-17A positive cells, mainly Th17 and γδ T lymphocytes, were found. Overall, the results support a pathogenic role of IL-17A in hypertensive kidney disease-associated inflammation. Therapeutic approaches targeting this cytokine should be explored to prevent hypertension-induced kidney injury.

Interleukin-17A blockade reduces albuminuria and kidney injury in an accelerated model of diabetic nephropathy.

Diabetic nephropathy (DN) is one of the most common complications of diabetes, and currently the first end-stage renal disease worldwide. New strategies to treat DN using agents that target inflammatory pathways have attracted special interest. Recent pieces of evidences suggest a promising effect of IL-17A, the Th17 effector cytokine. Among experimental DN models, mouse strain BTBR ob/ob (leptin deficiency mutation) develops histological features similar to human DN, which means an opportunity to study mechanisms and novel therapies aimed at DN regression. We found that BTBR ob/ob mice presented renal activation of the factors controlling Th17 differentiation. The presence of IL-17A-expressing cells, mainly CD4+ and γδ lymphocytes, was associated with upregulation of proinflammatory factors, macrophage infiltration and the beginning of renal damage. To study IL-17A involvement in experimental DN pathogenesis, treatment with an IL-17A neutralizing antibody was carried out starting when the renal damage had already appeared. IL-17A blockade ameliorated renal dysfunction and disease progression in BTBR ob/ob mice. These beneficial effects correlated to podocyte number restoration and inhibition of NF-κB/proinflammatory factors linked to a decrease in renal inflammatory-cell infiltration. These data demonstrate that IL-17A takes part in diabetes-mediated renal damage and could be a promising therapeutic target to improve DN.

Gremlin Regulates Tubular Epithelial to Mesenchymal Transition via VEGFR2: Potential Role in Renal Fibrosis.

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-ß 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.

Análisis de la vía Notch como una posible diana terapéutica en la patología renal / Could Notch signaling pathway be a potential therapeutic option in renal diseases?

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-κB 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

Could Notch signaling pathway be a potential therapeutic option in renal diseases? / Análisis de la vía Notch como una posible diana terapéutica en la patología 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-κB 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.

TGF-Beta Blockade Increases Renal Inflammation Caused by the C-Terminal Module of the CCN2.

The CCN family member 2 (CCN2, also known as connective tissue growth factor) may behave as a risk biomarker and a potential therapeutic target for renal disease. CCN2 participates in the regulation of inflammation and fibrosis. TGF-ß is considered the main fibrogenic cytokine; however, in some pathological settings TGF-ß also has anti-inflammatory properties. CCN2 has been proposed as a downstream profibrotic mediator of TGF-ß, but data on TGF-ß role in CCN2 actions are scarce. Our aim was to evaluate the effect of TGF-ß blockade in CCN2-mediated experimental renal damage. Systemic administration of the C-terminal module of CCN2 to mice caused sustained renal inflammation. In these mice, TGF-ß blockade, using an anti-TGF-ß neutralizing antibody, significantly increased renal expression of the NGAL (a kidney injury biomarker), kidney infiltration by monocytes/macrophages, and upregulation of MCP-1 expression. The anti-inflammatory effect of TGF-ß seems to be mediated by a dysregulation of the systemic Treg immune response, shown by decreased levels of circulating CD4(+)/Foxp3(+)Treg cells. Our experimental data support the idea that TGF-ß exerts anti-inflammatory actions in the kidney and suggest that it is not an optimal therapeutic target.