Colony stimulating factor-1 receptor drives glomerular parietal epithelial cell activation in focal segmental glomerulosclerosis.

Parietal epithelial cells (PECs) are kidney progenitor cells with similarities to a bone marrow stem cell niche. In focal segmental glomerulosclerosis (FSGS) PECs become activated and contribute to extracellular matrix deposition. Colony stimulating factor-1 (CSF-1), a hematopoietic growth factor, acts via its specific receptor, CSF-1R, and has been implicated in several glomerular diseases, although its role on PEC activation is unknown. Here, we found that CSF-1R was upregulated in PECs and podocytes in biopsies from patients with FSGS. Through in vitro studies, PECs were found to constitutively express CSF-1R. Incubation with CSF-1 induced CSF-1R upregulation and significant transcriptional regulation of genes involved in pathways associated with PEC activation. Specifically, CSF-1/CSF-1R activated the ERK1/2 signaling pathway and upregulated CD44 in PECs, while both ERK and CSF-1R inhibitors reduced CD44 expression. Functional studies showed that CSF-1 induced PEC proliferation and migration, while reducing the differentiation of PECs into podocytes. These results were validated in the Adriamycin-induced FSGS experimental mouse model. Importantly, treatment with either the CSF-1R-specific inhibitor GW2580 or Ki20227 provided a robust therapeutic effect. Thus, we provide evidence of the role of the CSF-1/CSF-1R pathway in PEC activation in FSGS, paving the way for future clinical studies investigating the therapeutic effect of CSF-1R inhibitors on patients with FSGS.

STING1 deficiency ameliorates immune-mediated crescentic glomerulonephritis in mice.

Rapidly progressive/crescentic glomerulonephritis (RPGN/CGN) involves the formation of glomerular crescents by maladaptive differentiation of parietal epithelial cells that leads to rapid loss of renal function. The molecular mechanisms of crescent formation are poorly understood. Therefore, new insights into molecular mechanisms could identify alternative therapeutic targets for RPGN/CGN. Analysis of kidney biopsies from patients with RPGN revealed increased interstitial, glomerular, and tubular expression of STING1, an accessory protein of the c-GAS-dependent DNA-sensing pathway, which was also observed in murine nephrotoxic nephritis induced by an anti-GBM antibody. STING1 was expressed by key cell types involved in RPGN and crescent formation such as glomerular parietal epithelial cells, and tubular cells as well as by inflammation accessory cells. In functional in vivo studies, Sting1-/- mice with nephrotoxic nephritis had lower kidney cytokine expression, milder kidney infiltration by innate and adaptive immune cells, and decreased disease severity. Pharmacological STING1 inhibition mirrored these findings. Direct STING1 agonism in parietal and tubular cells activated the NF-κB-dependent cytokine response and the interferon-induced genes (ISGs) program. These responses were also triggered in a STING1-dependent manner by the pro-inflammatory cytokine TWEAK. These results identify STING1 activation as a pathological mechanism in RPGN/CGN and TWEAK as an activator of STING1. Pharmacological strategies targeting STING1, or upstream regulators may therefore be potential alternatives to treat RPGN. © 2023 The Pathological Society of Great Britain and Ireland.

Intravascular hemolysis triggers NAFLD characterized by a deregulation of lipid metabolism and lipophagy blockade.

Intravascular hemolysis is a common feature of different clinical entities, including sickle cell disease and malaria. Chronic hemolytic disorders are associated with hepatic damage; however, it is unknown whether heme disturbs lipid metabolism and promotes liver steatosis, thereby favoring the progression to nonalcoholic fatty liver disease (NAFLD). Using an experimental model of acute intravascular hemolysis, we report here the presence of liver injury in association with microvesicular lipid droplet deposition. Hemolysis promoted serum hyperlipidemia and altered intrahepatic triglyceride fatty acid composition, with increments in oleic, palmitoleic, and palmitic acids. These findings were related to augmented expression of transporters involved in fatty acid uptake (CD36 and MSR1) and deregulation of LDL transport, as demonstrated by decreased levels of LDL receptor and increased PCSK9 expression. Hemolysis also upregulated hepatic enzymes associated with cholesterol biosynthesis (SREBP2, HMGC1, LCAT, SOAT1) and transcription factors regulating lipid metabolism (SREBP1). Increased LC3II/LC3I ratio and p62/SQSTM1 protein levels were reported in mice with intravascular hemolysis and hepatocytes stimulated with heme, indicating a blockade of lipophagy. In cultured hepatocytes, cell pretreatment with the autophagy inductor rapamycin diminished heme-mediated toxicity and accumulation of lipid droplets. In conclusion, intravascular hemolysis enhances liver damage by exacerbating lipid accumulation and blocking the lipophagy pathway, thereby promoting NAFLD. These new findings have a high translational potential as a novel NAFLD-promoting mechanism in individuals suffering from severe hemolysis episodes. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

A descriptive cross-sectional study on eating disorders, suicidal thoughts, and behaviors among adolescents in the Valencian community (Spain). The pivotal role of school nurses.

PURPOSE: The aims of this study were: 1) to describe the rates of risk of having an Eating Disorder (ED) and the rates of suicidal thoughts and behaviors, and 2) to examine the relationship between the risk of having an ED with suicidal thoughts and behaviors in adolescents enrolled in educational centers in the Community of Valencia (Spain). DESIGN AND METHODS: A cross-sectional study was conducted with 718 adolescents between September 2019 and July 2020 in five schools in the Community of Valencia (Spain). RESULTS: The adolescents studied, mostly females, are at risk of having an ED (18.6% to 30.8%) and experiencing suicidal thoughts (23% to 30.7%) and behaviors (2.2% to 6.2%). A strong association was found between EDs and suicidal thoughts and behaviors in both sexes. This association was higher in females with positive EAT-26 scores (OR: 2.09; 95% CI: 1.35-3.24) and in males with positive SCOFF scores (OR: 4.66; 95% CI: 2.40-9.02). Suicidal behaviors were positively associated with both EAT-26 (OR: 2.58; 95% CI: 1.17-5.67) and SCOFF (OR: 1.89; 95% CI: 1.21-2.26) scores in females. CONCLUSIONS: A considerable number of adolescents, females in particular, are at risk of having an ED and of experiencing suicidal thoughts and behaviors, establishing a strong link between EDs and suicidal tendencies. PRACTICAL IMPLICATIONS: The study highlights the importance of establishing national and regional regulations to ensure the availability of school nurses in the Community of Valencia (Spain). Collaboration between school nurses, educators, and policy makers is critical to the early detection of problems and the provision of support to both adolescents and families.

Targeting inflammation to treat diabetic kidney disease: the road to 2030.

Diabetic kidney disease (DKD) is one of the fastest growing causes of chronic kidney disease and associated morbidity and mortality. Preclinical research has demonstrated the involvement of inflammation in its pathogenesis and in the progression of kidney damage, supporting clinical trials designed to explore anti-inflammatory strategies. However, the recent success of sodium-glucose cotransporter-2 inhibitors and the nonsteroidal mineralocorticoid receptor antagonist finerenone has changed both guidelines and standard of care, rendering obsolete older studies directly targeting inflammatory mediators and the clinical development was discontinued for most anti-inflammatory drugs undergoing clinical trials for DKD in 2016. Given the contribution of inflammation to the pathogenesis of DKD, we review the impact on kidney inflammation of the current standard of care, therapies undergoing clinical trials, or repositioned drugs for DKD. Moreover, we review recent advances in the molecular regulation of inflammation in DKD and discuss potential novel therapeutic strategies with clinical relevance. Finally, we provide a road map for future research aimed at integrating the growing knowledge on inflammation and DKD into clinical practice to foster improvement of patient outcomes.

B- and T-lymphocyte attenuator could be a new player in accelerated atherosclerosis associated with chronic kidney disease.

BACKGROUND: In chronic kidney disease (CKD), cardiovascular morbi-mortality is higher than in general population. Atherosclerotic cardiovascular disease is accelerated in CKD, but specific CKD-related risk factors for atherosclerosis are unknown. METHODS: CKD patients from the NEFRONA study were used. We performed mRNA array from blood of patients free from atheroma plaque at baseline, with (n=10) and without (n=10) de novo atherosclerotic plaque development 2 years later. Selected mRNA candidates were validated in a bigger sample (n=148). Validated candidates were investigated in vivo in an experimental model of CKD-accelerated atherosclerosis, and in vitro in murine macrophages. RESULTS: mRNA array analysis showed 92 up-regulated and 67 down-regulated mRNAs in samples from CKD patients with de novo plaque development. The functional analysis pointed to a paramount role of the immune response. The validation in a bigger sample confirmed that B- and T-lymphocyte co-inhibitory molecule (BTLA) down-regulation was associated with de novo plaque presence after 2 years. However, BTLA down-regulation was not found to be associated with atherosclerotic progression in patients with plaque already present at baseline. In a model of CKD-accelerated atherosclerosis, mRNA and protein expression levels of BTLA were significantly decreased in blood samples and atheroma plaques. Plaques from animals with CKD were bigger, had more infiltration of inflammatory cells, higher expression of IL6 and IL17 and less presence of collagen than plaques from control animals. Incubation of macrophages with rat uremic serum decreased BTLA expression. CONCLUSIONS: BTLA could be a potential biomarker or therapeutic target for atherosclerosis incidence in CKD patients.

Efficacy and safety of total lymphoid irradiation in different chronic lung allograft dysfunction phenotypes.

Total lymphoid irradiation (TLI) is an alternative treatment for chronic lung allograft dysfunction (CLAD). However, data regarding its efficacy and tolerance are scarce. This study included patients with CLAD treated with TLI at our center between 2011 and 2018. Clinical characteristics before and after TLI and related complications were analyzed. Forty patients with CLAD (twenty-nine bronchiolitis obliterans syndrome [BOS], nine restrictive allograft syndrome [RAS], and two mixed) were included. Significant attenuation of the forced expiratory volume in 1-sec (FEV1 ) decline slope was observed in all phenotypes, in both the BOS and RAS. The median FEV1 12, 6, and 3 months pre-TLI were as follows: 1980 (IQR 1720-2560), 1665 (IQR 1300-2340) and 1300 (IQR 1040-1740) ml (p < .001), while the median FEV1 at 3, 6, and 12 months post-TLI was 1110 (IQR 810-1440), 1130 (IQR 860-1470), and 1115 (IQR 865-1490) ml (p = .769). No dropouts due to radiation toxicity were observed. The mean survival according to the Karnofsky Performance Status Scale (KPS) >70 or ≤70 at baseline was 1837 (IQR 259-2522) versus 298 (IQR 128-554) days (p < .0001), respectively. In conclusion, TLI may stop FEV1 decline in both BOS and RAS. Moreover, a good KPS score may be an important prognostic factor.

Challenges for Economic Evaluations of Advanced Therapy Medicinal Products: A Systematic Review.

OBJECTIVES: Advanced therapy medicinal products (ATMPs) are drugs for human use for the treatment of chronic, degenerative, or life-threatening diseases that are based on genes, tissues, or cells. This article aimed to identify and critically review published economic analyses of ATMPs. METHODS: A systematic review of economic analyses of ATMPs was undertaken. Study characteristics, design, sources of data, resources and unit costs, modeling and extrapolation methods, study results, and sensitivity analyses were assessed. RESULTS: A total of 46 economic analyses of ATMP (from 45 articles) were included; 4 were cell therapy medicinal products, 33 gene therapy medicinal products, and 9 tissue-engineered products. 30 therapies had commercial marketing approval; 39 studies were cost-utility analysis, 5 were cost-effectiveness analysis, and 2 were cost only studies. Four studies predicted that the ATMP offered a step change in the management of the condition and 10 studies estimated that the ATMP would offer a lower mean cost. CONCLUSIONS: Comparison with historical controls, pooling of data, and use of techniques such as mixture cure fraction models should be used cautiously. Sensitivity analyses should be used across a plausible range of prices. Clinical studies need to be designed to align with health technology assessment requirements, including generic quality of life, and payers should aim for clarity of criteria. Regulators and national payers should aim for compatibility of registers to allow interchange of data. Given the increasing reliance on industry-funded economic analyses, careful critical review is recommended.

Catastrophic out-of-pocket payments for dental treatment: regional evidence from Spain.

BACKGROUND: To estimate the incidence and concentration of catastrophic out-of-pocket payments for healthcare and dental treatment, by region in Spain (calculated as the proportion of households needing to exceed a given threshold of their income to make these payments) in 2008, 2011 and 2015. METHODS: The data analysed were obtained from the Spanish Family Budget Survey reports for the years in question. The study method was that proposed by Wagstaff and van Doorslaer (2003), contrasting payments for dental treatment versus household income and considering thresholds of 10%, 20%, 30% and 40%, thus obtaining incidence rates. In addition, relevant sociodemographic variables were obtained for each household included in the study. RESULTS: With some regional heterogeneity, on average 4.75% of Spanish households spend more than 10% of their income on dental treatment, and 1.23% spend more than 40%. Thus, 38.67% of catastrophic out-of-pocket payments for dental services in Spain corresponds to payments at the 10% threshold. This value rises to 55.98% for a threshold of 40%. CONCLUSIONS: An important proportion of catastrophic out-of-pocket payments for health care in Spain corresponds to dental treatment, a service that has very limited availability under the Spanish NHS. This finding highlights the need to formulate policies aimed at enhancing dental cover, in order to reduce inequalities in health care and, consequently, enhance the population's quality of life and health status.

Bone Marrow-Derived RIPK3 Mediates Kidney Inflammation in Acute Kidney Injury.

BACKGROUND: Receptor-interacting protein kinase 3 (RIPK3), a component of necroptosis pathways, may have an independent role in inflammation. It has been unclear which RIPK3-expressing cells are responsible for the anti-inflammatory effect of overall Ripk3 deficiency and whether Ripk3 deficiency protects against kidney inflammation occurring in the absence of tubular cell death. METHODS: We used chimeric mice with bone marrow from wild-type and Ripk3-knockout mice to explore RIPK3's contribution to kidney inflammation in the presence of folic acid-induced acute kidney injury AKI (FA-AKI) or absence of AKI and kidney cell death (as seen in systemic administration of the cytokine TNF-like weak inducer of apoptosis [TWEAK]). RESULTS: Tubular and interstitial cell RIPK3 expressions were increased in murine AKI. Ripk3 deficiency decreased NF-κB activation and kidney inflammation in FA-AKI but did not prevent kidney failure. In the chimeric mice, RIPK3-expressing bone marrow-derived cells were required for early inflammation in FA-AKI. The NLRP3 inflammasome was not involved in RIPK3's proinflammatory effect. Systemic TWEAK administration induced kidney inflammation in wild-type but not Ripk3-deficient mice. In cell cultures, TWEAK increased RIPK3 expression in bone marrow-derived macrophages and tubular cells. RIPK3 mediated TWEAK-induced NF-κB activation and inflammatory responses in bone marrow-derived macrophages and dendritic cells and in Jurkat T cells; however, in tubular cells, RIPK3 mediated only TWEAK-induced Il-6 expression. Furthermore, conditioned media from TWEAK-exposed wild-type macrophages, but not from Ripk3-deficient macrophages, promoted proinflammatory responses in cultured tubular cells. CONCLUSIONS: RIPK3 mediates kidney inflammation independently from tubular cell death. Specific targeting of bone marrow-derived RIPK3 may limit kidney inflammation without the potential adverse effects of systemic RIPK3 targeting.

Mitochondrial Dysfunction in the Cardio-Renal Axis.

Cardiovascular disease (CVD) frequently complicates chronic kidney disease (CKD). The risk of all-cause mortality increases from 20% to 500% in patients who suffer both conditions; this is referred to as the so-called cardio-renal syndrome (CRS). Preclinical studies have described the key role of mitochondrial dysfunction in cardiovascular and renal diseases, suggesting that maintaining mitochondrial homeostasis is a promising therapeutic strategy for CRS. In this review, we explore the malfunction of mitochondrial homeostasis (mitochondrial biogenesis, dynamics, oxidative stress, and mitophagy) and how it contributes to the development and progression of the main vascular pathologies that could be affected by kidney injury and vice versa, and how this knowledge may guide the development of novel therapeutic strategies in CRS.

Novel Aspects of the Immune Response Involved in the Peritoneal Damage in Chronic Kidney Disease Patients under Dialysis.

Chronic kidney disease (CKD) incidence is growing worldwide, with a significant percentage of CKD patients reaching end-stage renal disease (ESRD) and requiring kidney replacement therapies (KRT). Peritoneal dialysis (PD) is a convenient KRT presenting benefices as home therapy. In PD patients, the peritoneum is chronically exposed to PD fluids containing supraphysiologic concentrations of glucose or other osmotic agents, leading to the activation of cellular and molecular processes of damage, including inflammation and fibrosis. Importantly, peritonitis episodes enhance peritoneum inflammation status and accelerate peritoneal injury. Here, we review the role of immune cells in the damage of the peritoneal membrane (PM) by repeated exposure to PD fluids during KRT as well as by bacterial or viral infections. We also discuss the anti-inflammatory properties of current clinical treatments of CKD patients in KRT and their potential effect on preserving PM integrity. Finally, given the current importance of coronavirus disease 2019 (COVID-19) disease, we also analyze here the implications of this disease in CKD and KRT.

Paid and unpaid productivity losses due to premature mortality from cancer in Europe in 2018.

When someone dies prematurely from cancer this represents a loss of productivity for society. This loss can be valued and provides a measure of the cancer burden. We estimated paid and unpaid productivity lost due to cancer-related premature mortality in 31 European countries in 2018. Lost productivity was estimated for all cancers combined and 23 cancer sites, overall, by region and country. Deaths aged 15 to 64 were abstracted from GLOBOCAN 2018. Unpaid time lost (housework, caring, volunteering) was derived from Eurostat. Paid and unpaid productivity losses were valued using the human capital approach. In total, 347,149 premature cancer deaths occurred (60% male). The total value of cancer-related lost productivity was €104.6 billion. Of this, €52.9 billion (50.6%) was due to lost paid work, and €51.7 billion (49.4%) to unpaid work. Females accounted for 36.7% of paid work costs but half (51.1%) of the unpaid work costs. Costs were highest in Western Europe (€52.0 billion). The most costly cancer was lung (€21.7 billion), followed by breast (€10.6 billion). The average loss per premature death was highest for Hodgkin's lymphoma (€506 345), melanoma (€450 694), brain cancer (€428 449) and leukaemia (€378 750). Cancer-related lost productivity costs are significant. Almost half are due to unpaid work losses, indicating the importance of considering both paid and unpaid labour in assessing the cancer economic burden. The high cost per premature death of some less common cancers illustrates the potential benefits that could accrue from investment in prevention and control of these cancers.

Cellular communication network 2 (connective tissue growth factor) aggravates acute DNA damage and subsequent DNA damage response-senescence-fibrosis following kidney ischemia reperfusion injury.

Chronic allograft dysfunction with progressive fibrosis of unknown cause remains a major issue after kidney transplantation, characterized by ischemia-reperfusion injury (IRI). One hypothesis to account for this is that spontaneous progressive tubulointerstitial fibrosis following IRI is driven by cellular senescence evolving from a prolonged, unresolved DNA damage response (DDR). Since cellular communication network factor 2 ((CCN2), formerly called connective tissue growth factor), an established mediator of kidney fibrosis, is also involved in senescence-associated pathways, we investigated the relation between CCN2 and cellular senescence following kidney transplantation. Tubular CCN2 overexpression was found to be associated with DDR, loss of kidney function and tubulointerstitial fibrosis in both the early and the late phase in human kidney allograft biopsies. Consistently, CCN2 deficient mice developed reduced senescence and tubulointerstitial fibrosis in the late phase; six weeks after experimental IRI. Moreover, tubular DDR markers and plasma urea were less elevated in CCN2 knockout than in wild-type mice. Finally, CCN2 administration or overexpression in epithelial cells induced upregulation of tubular senescence-associated genes including p21, while silencing of CCN2 alleviated DDR induced by anoxia-reoxygenation injury in cultured proximal tubule epithelial cells. Thus, our observations indicate that inhibition of CCN2 can mitigate IRI-induced acute kidney injury, DNA damage, and the subsequent DDR-senescence-fibrosis sequence. Hence, targeting CCN2 might help to protect the kidney from transplantation-associated post-IRI chronic kidney dysfunction.

Antifibrotic Agents for the Management of CKD: A Review.

Kidney fibrosis is a hallmark of chronic kidney disease (CKD) and a potential therapeutic target. However, there are conceptual and practical challenges to directly targeting kidney fibrosis. Whether fibrosis is mainly a cause or a consequence of CKD progression has been disputed. It is unclear whether specifically targeting fibrosis is feasible in clinical practice because most drugs that decrease fibrosis in preclinical models target additional and often multiple pathogenic pathways (eg, renin-angiotensin-aldosterone system blockade). Moreover, tools to assess whole-kidney fibrosis in routine clinical practice are lacking. Pirfenidone, a drug used for idiopathic pulmonary fibrosis, is undergoing a phase 2 trial for kidney fibrosis. Other drugs in use or being tested for idiopathic pulmonary fibrosis (eg, nintedanib, PRM-151, epigallocatechin gallate) are also potential candidates to treat kidney fibrosis. Novel therapeutic approaches may include antagomirs (eg, lademirsen) or drugs targeting interleukin 11 or NKD2 (WNT signaling pathway inhibitor). Reversing the dysfunctional tubular cell metabolism that leads to kidney fibrosis offers additional therapeutic opportunities. However, any future drug targeting fibrosis of the kidneys should demonstrate added benefit to a standard of care that combines renin-angiotensin system with mineralocorticoid receptor (eg, finerenone) blockade or with sodium/glucose cotransporter 2 inhibitors.

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.

Electrodermal activity response during seizures: A systematic review and meta-analysis.

INTRODUCTION: Wearable devices for continuous seizure monitoring have drawn increasing attention in the field of epilepsy research. One of the parameters recorded by these devices is electrodermal activity (EDA). The aim of this study was to systematically review the literature to estimate the incidence of electrodermal response during seizures. METHODS: We searched all articles recording concurrent EDA and EEG activity during the pre-ictal, ictal, and postictal periods in children and adults with epilepsy. Studies reporting the total number of seizures and number of seizures with an EDA response were included for a random-effects meta-analysis. RESULTS: Nineteen studies, including 550 participants and 1115 seizures were reviewed. All studies demonstrated an EDA increase during the ictal and postictal periods, while only three reported pre-ictal EDA responses. The meta-analysis showed a pooled EDA response incidence of 82/100 seizures (95% CI 70-91). Tonic-clonic seizures (both generalized tonic-clonic seizures (GTCS) and focal to bilateral tonic-clonic seizures (FBTCS)) elicited a more pronounced (higher and longer-lasting) EDA response when compared with focal seizures (excluding FBTCS). DISCUSSION: Epileptic seizures produce an electrodermal response detectable by wearable devices during the pre-ictal, ictal, and postictal periods. Further research is needed to better understand EDA changes and to analyze factors which may influence the EDA response.

Adherence to treatment for hypothyroidism in pregnancy and relationship with thyrotropin control: a retrospective observational cohort study.

BACKGROUND: Hypothyroidism is the second most common endocrinological disease during pregnancy, with percentages that can range between 3.2 and 5.5%. A good maternal and foetal health outcome depends on thyroid hormone replacement therapy. The goal of such therapy is to maintain thyrotropin (TSH) in a range that is specific for pregnant women and varies between the trimesters of pregnancy. In our study, we wanted to analyse the adherence to hypothyroidism treatment among pregnant women and to evaluate the degree of control of the disease. METHODS: We performed a retrospective observational cohort study in pregnant women between 2012 and 2018 in the Lleida health region. Therapeutic adherence was analysed by the proportion of days covered (PDC). The relationship with other variables was assessed using the regression coefficients and their 95% confidence interval (CI). RESULTS: We examined a sample of 17,281 women, representing more than 92% of the pregnant women in the Lleida health region in the period analysed. Among this sample, the mean prevalence of hypothyroidism was 6.52% (0.07% clinical and 6.45% subclinical). 3.3% of the 17,281 pregnant women were treated. Among them, the mean adherence score was 79.6 ± 22.2. Of these, 54% presented high adherence. The latter had a higher mean age and better TSH control, in comparison to the ones showing low adherence. CONCLUSIONS: Half of the treated patients had good adherence to treatment and a better TSH control, in comparison to the others. Most of them achieved a good control at the third trimester of pregnancy.

The CCN2 Polymorphism rs12526196 Is a Risk Factor for Ascending Thoracic Aortic Aneurysm.

Cellular communication network factor 2 (CCN2/CTGF) has been traditionally described as a downstream mediator of other profibrotic factors including transforming growth factor (TGF)-ß and angiotensin II. However, recent evidence from our group demonstrated the direct role of CCN2 in maintaining aortic wall homeostasis and acute and lethal aortic aneurysm development induced by angiotensin II in the absence of CCN2 in mice. In order to translate these findings to humans, we evaluated the potential association between three polymorphisms in the CCN2 gene and the presence of a thoracic aortic aneurysm (TAA). Patients with and without TAA retrospectively selected were genotyped for rs6918698, rs9402373 and rs12526196 polymorphisms related to the CCN2 gene. Multivariable logistic regression models were performed. In our population of 366 patients (69 with TAA), no associations were found between rs6918698 and rs9402373 and TAA. However, the presence of one C allele from rs12526196 was associated with TAA comparing with the TT genotype, independently of risk factors such as sex, age, hypertension, type of valvulopathy and the presence of a bicuspid aortic valve (OR = 3.17; 95% CI = 1.30-7.88; p = 0.011). In conclusion, we demonstrated an association between the C allele of rs12526196 in the CCN2 gene and the presence of TAA. This study extrapolates to humans the relevance of CCN2 in aortic aneurysm observed in mice and postulates, for the first time, a potential protective role to CCN2 in aortic aneurysm pathology. Our results encourage future research to explore new variants in the CCN2 gene that could be predisposed to TAA development.

Type IV Collagen and SOX9 Are Molecular Targets of BET Inhibition in Experimental Glomerulosclerosis.

Progressive glomerulonephritis (GN) is characterized by an excessive accumulation of extracellular (ECM) proteins, mainly type IV collagen (COLIV), in the glomerulus leading to glomerulosclerosis. The current therapeutic approach to GN is suboptimal. Epigenetic drugs could be novel therapeutic options for human disease. Among these drugs, bromodomain and extra-terminal domain (BET) inhibitors (iBETs) have shown beneficial effects in experimental kidney disease and fibrotic disorders. Sex-determining region Y-box 9 (SOX9) is a transcription factor involved in regulating proliferation, migration, and regeneration, but its role in kidney fibrosis is still unclear. We investigated whether iBETs could regulate ECM accumulation in experimental GN and evaluated the role of SOX9 in this process. For this purpose, we tested the iBET JQ1 in mice with anti-glomerular basement membrane nephritis induced by nephrotoxic serum (NTS). In NTS-injected mice, JQ1 treatment reduced glomerular ECM deposition, mainly by inhibiting glomerular COLIV accumulation and Col4a3 gene overexpression. Moreover, chromatin immunoprecipitation assays demonstrated that JQ1 inhibited the recruitment and binding of BRD4 to the Col4a3 promoter and reduced its transcription. Active SOX9 was found in the nuclei of glomerular cells of NTS-injured kidneys, mainly in COLIV-stained regions. JQ1 treatment blocked SOX9 nuclear translocation in injured kidneys. Moreover, in vitro JQ1 blocked TGF-ß1-induced SOX9 activation and ECM production in cultured mesangial cells. Additionally, SOX9 gene silencing inhibited ECM production, including COLIV production. Our results demonstrated that JQ1 inhibited SOX9/COLIV, to reduce experimental glomerulosclerosis, supporting further research of iBET as a potential therapeutic option in progressive glomerulosclerosis.