Aim: Sexual dimorphisms are evident along the nephron: Females (F) exhibit higher ratios of renal distal to proximal Na + transporters' abundance, greater lithium clearance (C Li ) more rapid natriuresis in response to saline infusion and lower plasma [K + ] vs. males (M). During angiotensin II infusion hypertension (AngII-HTN) M exhibit distal Na + transporter activation, lower proximal and medullary loop transporters, blunted natriuresis in response to saline load, and reduced plasma [K + ]. This study aimed to determine whether responses of F to AngII-HTN mimicked those in M or were impacted by sexual dimorphisms evident at baseline. Methods: Sprague Dawley rats and C57BL/6 mice were AngII infused via osmotic minipumps 2 and 3 weeks, respectively, and assessed by metabolic cage collections, tail-cuff sphygmomanometer, semi-quantitative immunoblotting of kidney and patch-clamp electrophysiology. Results: In F rats, AngII-infusion increased BP to 190 mm Hg, increased phosphorylation of cortical NKCC2, NCC and cleavage of ENaC two to threefold, increased ENaC channel activity threefold and aldosterone 10-fold. K + excretion increased and plasma [K + ] decreased. Evidence of natriuresis in F included increased urine Na + excretion and C Li , and decreased medullary NHE3, NKCC2 and Na,K-ATPase abundance. In C57BL/6 mice, AngII-HTN increased abundance of distal Na + transporters, suppressed proximal-medullary transporters and reduced plasma [K + ] in both F and M. Conclusion: Despite baseline sexual dimorphisms, AngII-HTN provokes similar increases in BP, aldosterone, distal transporters, ENaC channel activation and K + loss accompanied by similar suppression of proximal and loop Na + transporters, natriuresis and diuresis in females and males. K E Y W O R D S angiotensin II, ENaC, female, potassium, proteinuria, sodium transport 2 of 12 | VEIRAS Et Al.

One in 8 women will develop breast cancer in their lifetime. Yet, the burden of disease is greater in Black women. Black women have a 40% higher mortality rate compared to White women, and a higher incidence of breast cancer at age 40 and younger. While the underlying cause of this disparity is multifactorial, exposure to endocrine disrupting chemicals (EDCs) in hair and other personal care products has been associated with an increased risk of breast cancer. Parabens are known EDCs that are commonly used as preservatives in hair and other personal care products, and Black women are disproportionately exposed to products containing parabens. Studies have shown that parabens impact breast cancer cell proliferation, death, migration/invasion, and metabolism, as well as gene expression in vitro. However, these studies were conducted using cell lines of European ancestry; to date, no studies have utilized breast cancer cell lines of West African ancestry to examine the effects of parabens on breast cancer progression. Like breast cancer cell lines with European ancestry, we hypothesize that parabens promote pro-tumorigenic effects in breast cancer cell lines of West African ancestry. Luminal breast cancer cell lines with West African ancestry (HCC1500) and European ancestry (MCF-7) were treated with biologically relevant doses of methylparaben, propylparaben, and butylparaben. Following treatment, estrogen receptor target gene expression and cell viability were examined. We observed altered estrogen receptor target gene expression and cell viability that was paraben- and cell-line specific. This study provides greater insight into the tumorigenic role of parabens in the progression of breast cancer in Black women.

Non-alcoholic fatty liver disease (NAFLD), and resultant non-alcoholic steatohepatitis (NASH), incidence and prevalence are rising globally due to increasing rates of obesity and diabetes. Currently, there are no approved pharmacological treatments for NAFLD, highlighting a need for additional mechanistic studies to develop prevention and/or therapeutic strategies. Diet-induced preclinical models of NAFLD can be used to examine the dynamic changes that occur during NAFLD development and progression throughout the lifespan. To date, most studies utilizing such models have focused exclusively on terminal time points and have likely missed critical early and late changes that are important for NAFLD progression (i.e, worsening). We performed a longitudinal analysis of histopathological, biochemical, transcriptomic, and microbiome changes that occurred in adult male mice fed either a control diet or a NASH-promoting diet (high in fat, fructose, and cholesterol) for up to 30 weeks. We observed progressive development of NAFLD in mice fed the NASH diet compared to the control diet. Differential expression of immune-related genes was observed at an early stage of diet-induced NAFLD development (10 weeks) and persisted into the later stages of the disease (20 and 30 weeks). Differential expression of xenobiotic metabolism related genes was observed at the late stage of diet-induced NAFLD development (30 weeks). Microbiome analysis revealed an increased abundance of Bacteroides at an early stage (10 weeks) that persisted into the later stages of the disease (20 and 30 weeks). These data provide insight into the progressive changes that occur during NAFLD/NASH development and progression in the context of a typical Western diet. Furthermore, these data are consistent with what has been reported in patients with NAFLD/NASH, supporting the preclinical use of this diet-induced model for development of strategies to prevent or treat the disease.

One in 8 women will develop breast cancer in their lifetime. Yet, the burden of disease is greater in Black women. Black women have a 40% higher mortality rate compared to White women, and a higher incidence of breast cancer at age 40 and younger. While the underlying cause of this disparity is multifactorial, exposure to endocrine disrupting chemicals (EDCs) in hair and other personal care products has been associated with an increased risk of breast cancer. Parabens are known EDCs that are commonly used as preservatives in hair and other personal care products, and Black women are disproportionately exposed to products containing EDCs. Studies have shown that parabens impact breast cancer cell proliferation, death, migration/invasion, and metabolism, as well as gene expression in vitro. However, these studies were conducted using cell lines of European ancestry; to date, no studies have utilized breast cancer cell lines of West African ancestry to examine the effects of parabens on breast cancer progression. Like breast cancer cell lines with European ancestry, we hypothesize that parabens promote pro-tumorigenic effects in breast cancer cell lines of West African ancestry. Luminal breast cancer cell lines with West African ancestry (HCC1500) and European ancestry (MCF-7) were treated with biologically relevant doses of methylparaben, propylparaben, and butylparaben. Following treatment, estrogen receptor target gene expression and cell viability were examined. We observed altered estrogen receptor target gene expression and cell viability that was paraben- and cell-line specific. This study provides greater insight into the tumorigenic role of parabens in the progression of breast cancer in Black women.

Experimental AngII hypertension is reported to be blunted in female (F) vs. male (M) mice and in mice lacking the inflammatory cytokine IL17A (time point dependent). This study aimed to determine how sex impacts renal Na+ transporters, Na+ and K+ excretion, and markers of renal injury during AngII hypertension (A) in both C57Bl/6 (WT) and IL17A−/− (IL17−/−) mice.11–16 wk old F and M mice were infused with AngII (490 ng/kg/min) or sham treated for 3 wk (n=6/group). Rate of excretion of a saline load (10% b.wt. subcutaneous) was slowed in all AngII infused groups, indicating Na+ reabsorption activation. Blood pressure (BP), by tail cuff, increased similarly across groups (in Δ mmHg): WTMA: 40 ± 1.6, WTFA: 37 ± 10, IL17−/−MA: 37 ± 3.8, IL17−/−FA: 46.4 ± 4.7. Thus, no blunting of hypertension was detected at 3 wk time point by tail cuff in F or in IL17−/−.In both M and F WT and IL17−/−, AngII provoked activation (‐phosphorylation) of NKCC2 and NCC, and activation of ENaC (more ‐cleaved (Cl), less full length (FL)). These distal anti‐natriuretic responses were balanced by natriuretic responses including: decreased abundance of proximal NHE3, NaPi2, and decreased medullary thick ascending limb NHE3, NKCC2 and NaK‐ATPase (see Figure). We previously proposed that increased ‐NCCp is a secondary compensation, driven by AngII activation of ENaC, to minimize K+ secretion (PMID27600183). Providing further support for this idea, urinary Na/K ratio (UNa/K), collected overnight (during fasting +water), was significantly reduced by AngII (WTM: from 0.71 ± 0.1 at baseline to 0.41 ± 0.9 with AngII, WTF: 0.80 ± 0.1 to 0.28 ±0.05, IL17−/−M: 0.99 ±0.13 to 0.41 ± 0.041, IL17−/−F: 1.05 ± 0.07 to 0.46 ± 0.46). UNa/K fell due to decreased o/n UNa as o/n UK was unaltered by AngII. Urine volume (V), unaltered by AngII treatment, was 2‐fold higher in M vs. F of both genotypes, and 2‐fold higher in IL17−/− vs. WT within each sex.During AngII, the injury marker U albumin increased across groups. Renal cortical angiotensinogen was lower in IL17−/− vs. WT (by 50% in F and 25% in M). KIM1 also tended to be lower in IL17−/− vs. WT in both sexes during AngII.From these results, we propose: AngII stimulation of ENaC drives UK secretion which activates NCCp (more in WT than IL17−/− males), thus reducing UNa to limit K secretion and lowering UNa/K which may contribute to BP elevation. IL17−/− mice exhibit higher UV and lower intrarenal angiotensinogen and KIM1 which suggests less tissue injury.Support or Funding InformationAHA GIA (15GRNT23160003) and an NIH NIDDK R01 (DK083785) to A.A. McDonough, NIH NHLBI K08 award (HL121671), Gilead Cardiovascular Scholars Grant, and NIH DP2 award (HL137166) to M.S. MadhurThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.