Adaptive immune response has been implicated in inflammation and fibrosis as a result of exposure to mineralocorticoids and a high-salt diet. We hypothesized that in mineralocorticoid-salt–induced hypertension, activation of the mineralocorticoid receptor alters the T-helper 17 lymphocyte (Th17)/regulatory T-lymphocyte/interleukin-17 (IL-17) pathway, contributing to cardiac and renal damage. We studied the inflammatory response and tissue damage in rats treated with deoxycorticosterone acetate and high-salt diet (DOCA–salt), with or without mineralocorticoid receptor inhibition by spironolactone. To determine whether Th17 differentiation in DOCA–salt rats is caused by hypertension per se, DOCA–salt rats received antihypertensive therapy. In addition, to evaluate the pathogenic role of IL-17 in hypertension and tissue damage, we studied the effect of IL-17 blockade with a specific antibody (anti–IL-17). We found activation of Th17 cells and downregulation of forkhead box P3 mRNA in peripheral tissues, heart, and kidneys of DOCA–salt–treated rats. Spironolactone treatment prevented Th17 cell activation and increased numbers of forkhead box P3–positive cells relative to DOCA–salt rats. Antihypertensive therapy did not ameliorate Th17 activation in rats. Treatment of DOCA–salt rats with anti–IL-17 significantly reduced arterial hypertension as well as expression of profibrotic and proinflammatory mediators and collagen deposits in the heart and kidney. We conclude that mineralocorticoid receptor activation alters the Th17/regulatory T-lymphocyte/IL-17 pathway in mineralocorticoid-dependent hypertension as part of an inflammatory mechanism contributing to fibrosis.

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Angiotensin-(1-9) reduces hypertension, ameliorates structural alterations (hypertrophy and fibrosis), oxidative stress in the heart and aorta and improves cardiac and endothelial function in hypertensive rats. These effects were mediated by the AT2 receptor but not by the angiotensin-(1-7)/Mas receptor axis.

Renal transplantation (RTx) is an effective therapy to improve clinical outcomes in pediatric patients with terminal chronic kidney disease. However, chronic immunosuppression with glucocorticoids (GCs) reduces bone growth and BMD. The mechanisms causing GC-induced growth impairment have not been fully clarified. Fibroblast growth factor 23 (FGF23) is a peptide hormone that regulates phosphate homeostasis and bone growth. In pathological conditions, FGF23 excess or abnormal FGF receptors (FGFR) activity leads to bone growth impairment. Experimental data indicate that FGF23 expression is induced by chronic GC exposure. Therefore, we hypothesize that GCs impair bone growth by increasing FGF23 expression, which has direct effects on bone growth plate. In a post hoc analysis of a multicentric randomized clinical trial of prepubertal RTx children treated with early GC withdrawal or chronic GC treatment, we observed that GC withdrawal was associated with improvement in longitudinal growth and BMD, and lower plasma FGF23 levels as compared with a chronic GC group. In prepubertal rats, GC-induced bone growth retardation correlated with increased plasma FGF23 and bone FGF23 expression. Additionally, GC treatment decreased FGFR1 expression whereas it increased FGFR3 expression in mouse tibia explants. The GC-induced bone growth impairment in tibiae explants was prevented by blockade of FGF23 receptors using either a pan-FGFR antagonist (PD173074), a C-terminal FGF23 peptide (FGF23180-205) which blocks the binding of FGF23 to the FGFR-Klotho complex or a specific FGFR3 antagonist (P3). Finally, local administration of PD173074 into the tibia growth plate ameliorated cartilage growth impairment in GC-treated rats. These results show that GC treatment partially reduces longitudinal bone growth via upregulation of FGF23 and FGFR3 expression, thus suggesting that the FGF23/Klotho/FGFR3 axis at the growth plate could be a potential therapeutic target for the management of GC-induced growth impairment in children.Intact plasma FGF23 levels were measured before RTx, and 1 week and 1 year after RTx ( Fig. 2A). Both groups had > 95% decrease in plasma FGF23 1 week after RTx, compared with baseline values, without differences between both groups. One year after RTx, SC patients had 3.2-fold higher plasma FGF23 levels compared with SW patients (1 year SC: 32.2 [24.0 to 45.7] pg/mL; 1 year SW: 10.1 [5.4 to 14.2] pg/mL; p < 0.001). When these FGF23 plasma levels were compared with a control group of healthy children ( Supplemental Table 3), SC patients had increased concentrations, but no significant differences compared with the ◼ 2 DELUCCHI ET AL. Fig. 4. Dexamethasone reduced growth of rat metatarsal explants, via fibroblast growth factor receptors (FGFRs). Prenatal rat metatarsal explants (extracted on E20) were cultured in the presence of dexamethasone (Dex; 1 nM); RU486 (RU; 25 μM), a glucocorticoid receptor antagonist; PD173074 (PD; 100 nM), a pan-FGFR antagonist; recombinant FGF23 (444 pM); or cell culture alone (Control), over ...

In the acrosome reaction, the spermatozoon plasma membrane fuses with the outer acrosomal membrane, resulting in the release of the acrosomal content. Several compounds, such as sex steroids, are known to modulate the acrosomal exocytosis. Testosterone regulates various functions in male reproductive physiology; however, little is known about the relationship between testosterone and the acrosome reaction. Thus, our objective was to study the effect of testosterone on the acrosome reaction of human spermatozoa. To evaluate the acrosomal exocytosis, spermatozoa were incubated with testosterone (0.2, 2.0 and 20 nmol l(-1)), progesterone and control medium for 60, 120, 240 and 1440 min. The acrosome reaction was assessed by staining with Hoechst 33258 and fluorescein isothiocyanate-conjugated P. sativum agglutinin lectin. In general, spermatozoa incubated with progesterone had the highest percentage of acrosomal exocytosis. The percentage of acrosome reaction obtained in the three treatments with testosterone differed from that observed for progesterone at 120, 240 and 1440 min (24 h). Additionally, significant differences were found between testosterone (2.0 and 20 nmol l(-1)) and progesterone after 60 min. Differences between control and the three testosterone treatments studied were obtained only at 1440 min. In general terms, these results show that testosterone exerts no inductor effects on the acrosome reaction of human spermatozoa.

Renal sodium reabsorption depends on the activity of the Na,K-ATPase α/β heterodimer. Four α (α) and 3 β (β) subunit isoforms have been described. It is accepted that renal tubule cells express α/β dimers. Aldosterone stimulates Na,K-ATPase activity and may modulate α/β expression. However, some studies suggest the presence of β in the kidney. We hypothesized that the β isoform of the Na,K-ATPase is expressed in tubular cells of the distal nephron, and modulated by mineralocorticoids. We found that β is highly expressed in collecting duct of rodents, and that mineralocorticoids decreased the expression of β. Thus, we describe a novel molecular mechanism of sodium pump modulation that may contribute to the effects of mineralocorticoids on sodium reabsorption.

Previously, we found in experimental hypertension (DOCA salt model), that the RhoA/Rho-kinase pathway inhibition by fasudil decreases hypertension (HT), angiotensin (Ang) II levels and vascular remodeling. Besides, in this model fasudil increased ACE2 activity and Ang1-9 plasma levels. These results strongly suggest that in this experimental model, ROCK activity is more dependent on ACE2 and Ang-(1-9) than Ang II levels. There is no current evidence regarding the effect of Ang1-9 on ROCK activity of hypertensive rats. Aim: To determine the effect of the chronic administration of Ang1-9 on blood pressure (BP), vascular damage and activation of RhoA/ROCK pathway in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Methods: The DOCA-salt hypertensive model was used in Sprague-Dawley male rats (age: 5-6 weeks; 150±10 g). DOCA was administered twice a week (60 mg/kg, im) starting immediately after surgery. The animals also received 1% NaCl and 0.4% KCl in the drinking water. Controls (C) were uninephrectomized rats (Sham group, n=12). Hypertensive rats (D) were randomized to receive vehicle (n=10), Ang-(1-9) (600 ng/kg/min, n=12), Ang-(1-9) + the Mas blocker receptor A779 (100 ng kg−1 min−1,n=7) and Ang-(1-9) + the AT2R antagonist PD123319 (PD, 36 ng/Kg min) for 2 weeks. Systolic (S) and diastolic (D) BP, body mass (BM), heart weight (HW), heart mass relative to the length of the tibia (HMR), lumen area (LA), vascular reactivity assays (VRA % dilation at 10-9M AcCh) and ROCK activity by the ratio of phosphorylated vs total MYPT1 (MP/ MT) in the aortic wall were determined. Results: Compared to sham rats, in hypertensive rats VRA was significantly decreased (C: 15 ± 1.8 vs D: 2 ± 0.8), whereas SBP (C: 125 ± 2 vs D: 207 ± 7), AMT/LA (C: 0.32 ± 0.01 vs D: 0.4 ± 0.01) and MP/ MT (C: 1 ± 0.12 vs D: 1.77 ± 0.38) were significantly increased. In DOCA hypertensive rats, Ang1-9 significantly reduced SBP (161 ± 6), AMT/LA (0.37 ± 0.01) and aortic MP/ MT (0.65 ± 0.07) but increased VRA (25 ± 1.1). These beneficial effects of Ang-(1-9) were modified by PD123319 but not by A779. Conclusion: Ang1-9 reduces BP and vascular damage by inhibiting ROCK activity in this model of low renin HT. These effects seem be mediated by the AT2R. Fondecyt 1100874 and 1121060.

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