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The Seventeenth International Conference on Endothelin (ET-17) was held during 4-7 October 2021. Among all the International ET conferences, this one was unique as it was held virtually. Because of [...], The Seventeenth International Conference on Endothelin (ET-17) was held during 4-7 October 2021 and because of the SARS-CoV-2 pandemic it was held virtually. Sponsored by the American Physiological Society, ET-17 was held over 4 half- days, with exciting studies related to all organ systems presented. Since the Lancet article reporting the successful SONAR clinical trial with endothelin receptor A blockade in diabetic nephropathy, there has been renewed interest in the use of endothelin receptor antagonists in the treatment of a variety of diseases. From the rigorous preclinical studies to the latest clinical trials, ET-17 was full of exciting science, some of which is reported in this special issue. We welcomed new labs to the meeting and everyone left with the impression that ET-related research is a vibrant field with very significant discoveries being made. Key words: endothelin Le Dix-septieme congres international sur l'endotheline (ET-17) a eu lieu du 4 au 7 octobre 2021, de maniere virtuelle en raison de la pandemie du SARS-CoV-2. Soutenu par l'American Physiological Society, l'ET-17 s'est tenu sur 4 demi- journees, avec la presentation d'etudes sensationnelles portant sur tous les systemes organiques. Depuis l'article du Lancet rapportant les succes de l'essai clinique SONAR sur l'inhibition du recepteur A de l'endotheline dans la nephropathie diabetique, on a assiste a un interet renouvele pour l'utilisation d'antagonistes des recepteurs de l'endotheline dans le traitement de toute une variete de maladies. Des etudes precliniques rigoureuses jusqu'aux plus recents essais cliniques, l'ET-17 etait pleinement anime de travaux scientifiques palpitants, dont certains sont rapportes dans le present numero special. Nous avons accueilli au congres de nouveaux laboratoires et nous nous sommes tous quittes avec l'impression que la recherche sur l'endotheline est un champ d'activite tres dynamique oU s'accomplissent des decouvertes majeures. Mots-cles : endotheline

Introduction The endothelin (ET) system is composed of three different peptides ET-1 (gene Edn1), ET-2 (Edn2), and ET-3 (Edn3) that undergo proteolytic cleavage by the ET converting enzymes (Ece1 and [...], The chemotherapeutic agent cisplatin accumulates in the kidney and induces acute kidney injury (AKI). Preclinical and clinical studies suggest that young female mice and women show greater recovery from cisplatin-AKI compared to young male mice and men. The endothelin (ET) and ET receptors are enriched in the kidney and may be dysfunctional in cisplatin-AKI; however, there is a gap in our knowledge about the putative effects of sex and cisplatin on the renal ET system. We hypothesized that cisplatin-AKI male and female mice will have increased expression of the renal ET system. As expected, all cisplatin-AKI mice had kidney damage and body weight loss greater than control mice. Cisplatin-AKI mice had greater cortical Edn1, Edn3, Ednra, and Ednrb, while outer medullary Ednra was significantly suppressed in both sexes. Of the ~25 000 genes sequenced from the inner medulla, only 91 genes (comparing salinemice) and 134 genes (comparing cisplatin-AKI mice) were differentially expressed and they were unrelated to the ET system. However, Edn1 was significantly greater in the inner medulla of male and female cisplatin-AKI mice. Thus, RNA profiles of the ET system were significantly affected by cisplatin-AKI throughout the kidney regardless of sex and this may help determine the therapeutic potential of targeting the ET receptors in cisplatin-AKI. Key words: endothelin, kidney, RNA, cisplatin, acute kidney injury, sex Le cisplatine, un agent chimiotherapeutique, s'accumule dans le rein, ou il entraine des lesions renales aigues (LRA). Les etudes precliniques et cliniques laissent entendre que les jeunes souris femelles et les jeunes femmes parviendraient mieux a se retablir de la situation cisplatine-LRA que les jeunes males et les jeunes hommes. L'endotheline (ET) et les recepteurs de l'ET sont plus presents dans les reins et pourraient etre dysfonctionnels en situation cisplatine-LRA; cependant nos connaissances quant aux effets eventuels du sexe et du cisplatine dans le systeme ET renal sont lacunaires. Nous avons formule une hypothese selon laquelle l'expression du systeme ET renal est accrue chez les souris males et femelles cisplatine-LRA. Comme prevu, les souris cisplatine-LRA presentaient toutes des lesions renales et une perte de poids plus importantes que les souris temoin. Les souris cisplatine-LRA exprimaient Edn1, Edn3, Ednra, et Ednrb dans le cortex dans une plus grande mesure, tandis qu'Ednra etait nettement inhibe chez les deux sexes. Parmi environ 25 000 genes sequences dans la medulla interne, uniquement 91 genes (comparaison avec les souris solution saline) et 134 genes (comparaison avec les souris cisplatine-LRA) s'exprimaient de maniere differentielle, et ils n'etaient pas lies au systeme ET. Cependant, Edn1 s'exprimait nettement plus dans la medulla interne des souris cisplatine-LRA males et femelles. Par consequent, les profils du systeme ET en ARN etaient affectes de facon marquee avec le couple cisplatine-LRA a l'echelle du rein entier, sans egard au sexe. Cette observation pourrait contribuer a etablir le potentiel therapeutique du ciblage des recepteurs de l'ET en situation cisplatine-LRA. Mots-cles : endotheline, reins, ARN, cisplatine, lesions renales aigues, sexe

The chemotherapeutic agent cisplatin accumulates in the kidneys, leading to acute kidney injury (AKI). Preclinical and clinical studies have demonstrated sex-dependent outcomes of cisplatin-AKI. Deranged histone deacetylase (HDAC) activity is hypothesized to promote the pathogenesis of male murine cisplatin-AKI; however, it is unknown whether there are sex differences in the kidney HDACs. We hypothesized that there would be sex-specific Hdac expression, localization, or enzymatic activity, which may explain sexual dimorphic responses to cisplatin-AKI. In normal human kidney RNA samples, HDAC10 was significantly greater in the kidneys of women compared with men, whereas HDAC1, HDAC6, HDAC10, and HDAC11 were differentially expressed between the kidney cortex and medulla, regardless of sex. In a murine model of cisplatin-AKI (3 days after a 15 mg/kg injection), we found few sex- or cisplatin-related differences in Hdac kidney transcripts among the mice. Although Hdac9 was significantly greater in female mice compared with male mice, HDAC9 protein localization did not differ. Hdac7 transcripts were greater in the inner medulla of cisplatin-AKI mice, regardless of sex, and this agreed with a greater HDAC7 abundance. HDAC activity within the cortex, outer medulla, and inner medulla was significantly lower in cisplatin-AKI mice but did not differ between the sexes. In agreement with these findings, a class I HDAC inhibitor did not improve kidney injury or function. In conclusion, even though cisplatin-AKI was evident and there were transcript level differences among the different kidney regions in this model, there were few sex- or cisplatin-dependent effects on kidney HDAC localization or activity. NEW & NOTEWORTHY: Kidney histone deacetylases (HDACs) are abundant in male and female mice, and the inner medulla has the greatest HDAC activity. A low dose of cisplatin caused acute kidney injury (AKI) in these mice, but there were few changes in kidney HDACs at the RNA/protein/activity level. A class I HDAC inhibitor failed to improve AKI outcomes. Defining the HDAC isoform, cellular source, and interventional timing is necessary to determine whether HDAC inhibition is a therapeutic strategy to prevent cisplatin-AKI in both sexes. [ABSTRACT FROM AUTHOR]

Aims: Endothelin‐1 (ET‐1) is elevated in patients with obesity and adipose tissue of obese mice fed high‐fat diet (HFD); however, its contribution to the pathophysiology of obesity is not fully understood. Genetic loss of endothelin type B receptors (ETB) improves insulin sensitivity in rats and leads to increased circulating adiponectin, suggesting that ETB activation on adipocytes may contribute to obesity pathophysiology. We hypothesized that elevated ET‐1 in obesity promotes insulin resistance by reducing the secretion of insulin sensitizing adipokines, via ETB receptor. Methods: Male adipocyte‐specific ETB receptor knockout (adETBKO), overexpression (adETBOX), or control littermates were fed either normal diet (NMD) or high‐fat diet (HFD) for 8 weeks. Results: RNA‐sequencing of epididymal adipose (eWAT) indicated differential expression of over 5500 genes (p < 0.05) in HFD compared to NMD controls, and changes in 1077 of these genes were attenuated in HFD adETBKO mice. KEGG analysis indicated significant increase in metabolic signaling pathway. HFD adETBKO mice had significantly improved glucose and insulin tolerance compared to HFD control. In addition, adETBKO attenuated changes in plasma adiponectin, insulin, and leptin that is observed in HFD versus NMD control mice. Treatment of primary adipocytes with ET‐1 caused a reduction in adiponectin production that was attenuated in cells pretreated with an ETB antagonist. Conclusion: These data indicate elevated ET‐1 in adipose tissue of mice fed HFD inhibits adiponectin production and causes insulin resistance through activation of the ETB receptor on adipocytes. [ABSTRACT FROM AUTHOR]

Introduction Global dietary sodium intake as of 2010 has increased to ~3.95 g/day, nearly twice the recommended limit of 2 g/day established by the World Health Organization (Powles et al. [...], High salt intake (HS) is associated with obesity and insulin resistance. ET-1, a peptide released in response to HS, inhibits the actions of insulin on cultured adipocytes through ET-1 type B (ETB) receptors; however, the in vivo implications of ETB receptor activation on lipid metabolism and insulin resistance is unknown. We hypothesized that activation of ETB receptors in response to HS intake promotes dyslipidemia and insulin resistance. In normal salt (NS) fed rats, no significant difference in body mass or epididymal fat mass was observed between control and ETB deficient rats. After 2 weeks of HS, ETB-deficient rats had significantly lower body mass and epididymal fat mass compared to controls. Nonfasting plasma glucose was not different between genotypes; however, plasma insulin concentration was significantly lower in ETB-deficient rats compared to controls, suggesting improved insulin sensitivity. In addition, ETB-deficient rats had higher circulating free fatty acids in both NS and HS groups, with no difference in plasma triglycerides between genotypes. In a separate experiment, ETB-deficient rats had significantly lower fasting blood glucose and improved glucose and insulin tolerance compared to controls. These data suggest that ET-1 promotes adipose deposition and insulin resistance via the ETB receptor. Key words: insulin resistance, salt intake, lipids. L'apport sodique eleve (HS) est associe a l'obesite et a la resistance a l'insuline. L'ET-1, un peptide libere en reaction au SE, entraine une inhibition de l'action de l'insuline dans des adipocytes en culture par l'intermediaire des recepteurs de l'ET-1 de type B (RETB); cependant, le role que joue l'activation des RETB sur le metabolisme des lipides et la resistance a l'insuline in vivo est inconnu. Nous avons pose l'hypothese selon laquelle l'activation des RETB dans la reaction a l'apport HS favorise la dyslipidemie et la resistance a l'insuline. Chez des rats auxquels etait administre un apport sodique normal (NS), nous n'avons observe aucune difference notable du poids corporel ou de la masse adipeuse de l'epididyme entre les temoins et les rats presentant un deficit en RETB. Apres 2 semaines avec HS, les rats avec un deficit en RETB presentaient une diminution nettement plus importante du poids corporel et de la masse adipeuse de l'epididyme que les temoins. La glycemie non a jeun n'etait pas differente entre les genotypes, mais les concentrations d'insuline plasmatique etaient nettement moins elevees chez les rats avec deficit en RETB que chez les temoins, ce qui laisse entrevoir la presence eventuelle d'une amelioration de la sensibilite a l'insuline. De plus, les rats avec deficit en RETB presentaient des taux d'acides gras libres en circulation plus eleves a la fois dans les groupes HS et NS, sans difference entre les genotypes quant aux taux de triglycerides plasmatiques. Dans des experiences a part, les rats avec deficit en RETB presentaient une glycemie a jeun nettement moins elevee ainsi qu'une amelioration marquee de la tolerance au glucose et a l'insuline que les temoins. Ces donnees laissent entendre que l'ET-1 favoriserait le depot de tissu adipeux et la resistance a l'insuline par l'intermediaire des RETB. [Traduit par la Redaction] Mots-cles: resistance a l'insuline, apport sodique, lipides.

Sepsis-associated acute kidney injury (SA-AKI) is a key contributor to the life-threatening sequelae attributed to sepsis. Mechanistically, SA-AKI is a consequence of unabated myeloid cell activation and oxidative stress that induces tubular injury. Iron mediates inflammatory pathways directly and through regulating the expression of myeloid-derived ferritin, an iron storage protein comprising ferritin light (FtL) and ferritin heavy chain (FtH) subunits. Previous work revealed that myeloid FtH deletion leads to a compensatory increase in intracellular and circulating FtL and is associated with amelioration of SA-AKI. We designed this study to test the hypothesis that loss of myeloid FtL and subsequently, circulating FtL will exacerbate the sepsis-induced inflammatory response and worsen SA-AKI. We generated a novel myeloid-specific FtL knockout mouse (FtLLysM-/-) and induced sepsis via cecal ligation and puncture or lipopolysaccharide endotoxemia. As expected, serum ferritin levels were significantly lower in the knockout mice, suggesting that myeloid cells dominantly contribute to circulating ferritin. Interestingly, although sepsis induction led to a marked production of pro- and anti-inflammatory cytokines, there was no statistical difference between the genotypes. There was a similar loss of kidney function, as evidenced by a rise in serum creatinine and cystatin C and renal injury identified by expression of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin. Finally, RNA sequencing revealed upregulation of pathways for cell cycle arrest and autophagy postsepsis, but no significant differences were observed between genotypes, including in key genes associated with ferroptosis, an iron-mediated form of cell death. The loss of FtL did not impact sepsis-mediated activation of NF-B or HIF-1a signaling, key inflammatory pathways associated with dysregulated host response. Taken together, while FtL overexpression was shown to be protective against sepsis, the loss of FtL did not influence sepsis pathogenesis. NEW & NOTEWORTHY Hyperferritinemia in sepsis is often associated with a proinflammatory phenotype and poor prognosis. We previously showed the myeloid deletion of FtH results in a compensatory increase in FtL and is associated with reduced circulating cytokines and decreased rates of SA-AKI in animal sepsis models. Here, we show that myeloid deletion of FtL does not impact the severity of SA-AKI following CLP or LPS, suggesting that FtH plays the predominant role in propagating myeloidinduced proinflammatory pathways. [ABSTRACT FROM AUTHOR]

The intrarenal endothelin (ET) system is an established moderator of kidney physiology and mechanistic contributor to the pathophysiology and progression of chronic kidney disease in humans and rodents. The aim of the present study was to characterize ET system by combining single cell RNA sequencing (scRNA-seq) data with immunolocalization in human and rodent kidneys of both sexes. Using publicly available scRNA-seq data, we assessed sex and kidney disease status (human), age and sex (rats), and diurnal expression (mice) on the kidney ET system expression. In normal human biopsies of both sexes and in rodent kidney samples, the endothelin-converting enzyme-1 (ECE1) and ET-1 were prominent in the glomeruli and endothelium. These data agreed with the scRNA-seq data from these three species, with ECE1/Ece1 mRNA enriched in the endothelium. However, the EDN1/Edn1 gene (encodes ET-1)was rarely detected, even though it was immunolocalized within the kidneys, and plasma and urinary ET-1 excretion are easily measured. Within each species, there were some sex-specific differences. For example, in kidney biopsies from living donors, men had a greater glomerular endothelial cell endothelin receptor B (Ednrb) compared with women. In mice, females had greater kidney endothelial cell Ednrb than male mice. As commercially available antibodies did not work in all species, and RNA expression did not always correlate with protein levels, multiple approaches should be considered to maintain required rigor and reproducibility of the pre- and clinical studies evaluating the intrarenal ET system. [ABSTRACT FROM AUTHOR]

The article focuses on investigating whether bottlenose dolphins' circulating factors offer protection against age-related endothelial dysfunction, drawing from their unique physiological adaptations. Topics include the impact of serum from bottlenose dolphins on endothelial function in mice, comparative vascular physiology in dolphins versus humans, and the potential for future studies to explore underlying mechanisms of endothelial protection through a multi-omics approach.

Daily, we may experience mild dehydration with a rise in plasma osmolality that triggers the release of vasopressin. Although the effect of dehydration is well characterized in collecting duct principal cells (CDPCs), we hypothesized that mild dehydration (<12 h) results in many kidney cell-specific changes in transcriptomes and chromatin accessibility. Single-nucleus (sn) multiome (RNA-assay for transposase-accessible chromatin) sequencing and bulk RNA sequencing of kidneys from male and female mice that were mildly water deprived or not were compared. Water-deprived mice had a significant increase in plasma osmolality. snmultiome-seq resulted in 19,837 nuclei that were annotated into 33 clusters. In CDPCs, aquaporin 2 (Aqp2) and aquaporin 3 (Apq3) were greater in dehydrated mice, but there were novel genes like gremlin 2 (Grem2; a cytokine) that were increased compared with ad libitum mice. The transcription factor cAMP-responsive element modulator (Crem) was greater in CDPCs of dehydrated mice, and the Crem DNA motif was more accessible. There were hundreds of sex- and dehydration-specific differentially expressed genes (DEGs) throughout the kidney, especially in the proximal tubules and thin limbs. In male mice, DEGs were enriched in pathways related to lipid metabolism, whereas female DEGs were enriched in organic acid metabolism. Many highly expressed genes had a positive correlation with increased chromatin accessibility, and mild dehydration exerted many transcriptional changes that we detected at the chromatin level. Even with a rise in plasma osmolality, male and female kidneys have distinct transcriptomes suggesting that there may be diverse mechanisms used to remain in fluid balance. NEW & NOTEWORTHY The kidney consists of >30 cell types that work collectively to maintain fluid-electrolyte balance. Kidney single-nucleus transcriptomes and chromatin accessibility profiles from male and female control (ad libitum water and food) or mildly dehydrated mice (ad libitum food, water deprivation) were determined. Mild dehydration caused hundreds of cell- and sex-specific transcriptomic changes, even though the kidney function to conserve water was the same. [ABSTRACT FROM AUTHOR]

Am J Physiol Regul Integr Comp Physiol 298: R61-R69, 2010. First published November 4, 2009; doi: 10.1152/ajpregu.00526.2009.--The goal of this study was to examine the status of the renal nitric oxide (NO) system by determining NO synthase (NOS) isoform activity and expression within the three regions of the kidney in 14-wk-old male and female spontaneously hypertensive rats (SHR). NOS activity, and NOS1 and NOS3 protein expressions and localization were comparable in the renal cortex and outer medulla of male and female SHR. In contrast, male SHR had significantly less NOS1 and NOS3 enzymatic activity (0 [+ or -] 5 and 53 [+ or -] 7 pmol x [mg.sup.-1] x 30 [min.sup.-1], respectively) compared with female SHR (37 [+ or -] 16 and 172 [+ or -] 40 pmol x [mg.sup.-l] x 30 [min.sup.-1], respectively). Lower levels of inner medullary NOS1 activity in male SHR were associated with less NOS1 protein expression [45 [+ or -] 7 relative densitometric units (RDU)] and fewer NOS1-positive cells in the renal inner medulla compared with female SHR (79 [+ or -] 12 RDU). Phosphorylation of NOS3 is an important determinant of NOS activity. Male SHR had significantly greater phosphorylation of NOS3 on threonine 495 in the renal cortex compared with females (0.25 [+ or -] 0.05 vs. 0.15 [+ or -] 0.06 RDU). NOS3 phosphorylation was comparable in males and females in the other regions of the kidney, cGMP levels were measured as an indirect index of NO production, cGMP levels were significantly lower in the renal cortex (0.08 [+ or -] 0.01 pmol/mg) and inner medulla (0.43 [+ or -] 0.[O.sub.2] pmol/mg) of male SHR compared with females (cortex: 0.14 [+ or -] 0.[O.sub.2] pmol/mg; inner medulla: 0.56 [+ or -] 0.[O.sub.2] pmol/mg). Our data suggest that the effect of the sex of the animal on NOS activity and expression is different in the three regions of the SHR kidney and supports the hypothesis that male SHR have lower NO bioavailability compared with females. nitric oxide synthase; kidney; sex; gender; cGMP