Renal immune cell infiltration and cells expressing angiotensin II (AII) in tubulointerstitial areas of the kidney are features of experimental models of salt-sensitive hypertension (SSHTN). A high-salt intake tends to suppress circulating AII levels, but intrarenal concentrations of AII have not been investigated in SSHTN. This study explored the relationship between these features to gain insight into the pathophysiology of SSHTN. Plasma angiotensin II (AII) and renal interstitial AII (microdialysis technique) and the infiltration of macrophages, lymphocytes, and AII-positive cells were determined in SSHTN induced by 5 wk of a high-salt diet (HSD) after short-term infusion of AII in rats with (n = 10) and without (n = 11) treatment with mycophenolate mofetil (MMF) and in control rats fed a high- (n = 7) and normal (n = 11) salt diet. As in previous studies, MMF did not affect AII-associated hypertension but reduced the interstitial inflammation and the SSHTN in the post-AII-period. During the HSD period, the AII group untreated with MMF had mean +/- SD) low plasma (2.4 +/- 1.4 pg/ml) and high interstitial AII concentration (1,310 +/- 208 pg/ml); MMF treatment resulted in a significantly lower interstitial AII (454 +/- 128 pg/ml). Renal AII concentration and the number of tubulointerstitial AII-positive cells were correlated. Blood pressure correlated positively with interstitial AII and negatively with plasma AII, thus giving compelling evidence of the paramount role of the AII within the kidney in the AII-induced model of salt-driven hypertension.

A B S T R A C T In order to obtain direct evidence for the existence of a natriuretic hormone, dialysates and ultrafiltrates of plasma of dogs expanded with saline were tested for effects on sodium transport by the toad urinary bladder. Dialysate was obtained by dialysis of blood in vivo in a clinical dialyzer and by dialysis in vitro of small volumes of blood using a miniature model of the clinical dialyzer. Ultrafiltrates were prepared using selective molecular filters which permit passage of substances on the basis of molecular weight and three dimensional configuration.Dialysates and ultrafiltrates of hydropenic dogs caused a change in toad bladder potential difference of + 1% and in short circuit current of -5%. In contrast, dialysates and ultrafiltrates from expanded dogs caused a change in potential difference of -23% and in short circuit current of -32%, a highly significant difference. Onset of reduction of short circuit current occurred within 3-5 min, reaching a maximum in 10-20 min. The effect was rapidly reversible, was specific for the serosal surface of the bladder, and could not be explained on the basis of nonspecific alterations in ionic composition or by dilutional effects. Ultrafiltrates of jugular vein plasma caused significantly more reduction of short circuit current than ultrafiltrates of femoral vein plasma. The data indicate the presence in plasma of saline-loaded dogs of a dialyzable inhibitor of toad bladder sodium transport. Ultrafiltrate studies using membranes of appropriate selectivity suggest the factor has a molecular weight of less than 3000.

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Transient administration of ANG II causes persistent salt-sensitive hypertension associated with arteriolopathy, interstitial inflammation, and cortical vasoconstriction; blocking the vascular and inflammatory changes with mycophenolate mofetil (MMF) prevents vasoconstriction. While infiltrating leukocytes during the salt-sensitive hypertension phase express ANG II, the functional role of ANG II during this phase is not known. We examined the acute effect of candesartan on renal hemodynamics during the established salt-sensitive hypertensive phase and related these findings to direct measurement of intrarenal ANG II and inflammatory cells in rats previously exposed to ANG II with or without MMF treatment. Sham controls were also examined. The administration of ANG II, followed by exposure to high-salt diet, resulted in hypertension, cortical vasoconstriction, an increase in interstitial inflammatory cells (44.8 +/- 1.3 lymphocytes/mm2, and 30.8 +/- 1.2 macrophages/mm2 ANG II vs. 19.6 +/- 2 lymphocytes/mm2, and 22 +/- 0.7 macrophages/mm2 Sham), and increase in renal ANG II levels (1,358 +/- 74.6 pg/ml ANG II vs. 194 +/- 9.28 pg/ml Sham). Treatment with MMF during the administration of exogenous ANG II resulted in reduction in renal interstitial inflammation (19.7 +/- 0.9 lymphocytes/mm2 and 15.9 +/- 0.8 machophages/mm2), ANG II levels (436.9 +/- 52.29 pg/ml), cortical vasoconstriction, and stable blood pressure levels during the subsequent challenge with a high-salt diet. Acute administration of candesartan similarly reduced renal vasoconstriction and blood pressure. We conclude that the cortical vasoconstriction occurring with salt-sensitive hypertension following exposure to ANG II is mediated by intrarenal ANG II, related, at least in part, to the interstitial inflammation.

Glucose uptake is increased in hypertension. Thus we investigated Na+-glucose cotransporter (SGLT2) activity and expression in proximal tubules from renovascular hypertensive rats. Sham-operated rats, aortic coarctation rats, and aortic coarctation rats treated with either ramipril (2.5 mg.kg-1.day-1 for 21 days) or losartan (10 mg.kg-1.day-1 for 21 days) were used. Na+-dependent glucose uptake was measured in brush-border membrane vesicles (BBMV). Vmax in BBMV from hypertensive rats was greater compared with those from normotensive rats (3 +/- 0.2 vs. 1.5 +/- 0.1 nmol.mg protein-1.min-1) without a change in Km. Renal immunostaining was greater, and Western blot analysis and RT-PCR showed a higher expression of SGLT2 in hypertensive rats than in normotensive rats (1,029 +/- 71 vs. 5,003 +/- 292, 199 +/- 15 vs. 95 +/- 10, and 1.4 +/- 0.2 vs. 0.3 +/- 0.1 arbitrary units, respectively). In rats treated with either ramipril or losartan, Vmax decreased to 2.1 +/- 0.3 and 1.8 +/- 0.4 nmol.mg protein-1.min-1, respectively, as well as did the intensity of immunostaining and levels of protein and mRNA. We suggest that in renovascular hypertension, angiotensin II induced SGLT2 via the AT1 receptor, which was evidenced at both the functional and expression levels, probably contributing to increased absorption of Na+ and thereby to the development or maintenance of hypertension.

Our findings show that BPA concentrations of 1 µM or higher decrease the survival of human fetal oocytes in vitro, and concentrations of 10 µM or higher increase MLH1 foci number. MLH1 is considered a CO marker, and thus an increase in MLH1 foci could indicate an increase in COs in BPA-exposed oocytes. These data suggest that BPA can act as a toxic substance, which has particular implications for human females and the critical events of meiotic prophase, such as pairing-synapsis and recombination processes, as well as oocyte survival.

The mechanisms involved in urate and p-aminohippurate (PAH) transport in the rabbit renal brush-border membrane were investigated through study of membrane vesicles. Transport of [14C]urate and [3H]PAH was measured by a rapid filtration method. As previously reported by others, no OH(-)-PAH exchanger could be demonstrated by imposing an outwardly directed OH- gradient (pHin 7.4, pHout 6). In contrast, an OH(-)-lactate exchanger (or H(+)-lactate cotransport) was demonstrated. In the presence of valinomycin and an inwardly directed K+ gradient, both [14C]urate and [3H]PAH vesicle uptake were stimulated, demonstrating a potential-driven transport of these two anions. Probenecid, PAH, or cold urate decreased potential-driven urate uptake, suggesting that this transport was facilitated by a specific transport mechanism. The potential-driven urate transport described here may play a role in the second step of urate secretion in rabbits, because rate (or PAH) is transported across the brush-border membrane from the negative interior of the cell to the more positive omen.

Bisphenol A (BPA) is a 'weak' endocrine disruptor. The effect of BPA on human reproduction is controversial but has been related to meiotic anomalies, recurrent spontaneous abortion, abnormal karyotypes, the diminishing of oocyte survival, delay in meiotic progression and an elevated rate of MLH1 foci in vitro. The aim of this study is to characterize the gene expression of human fetal oocytes in culture as well as to evaluate the effect of BPA in cultured human oocytes. To accomplish our objective, 12 ovaries from 6 euploid fetuses were used. The ovarian fetal tissue was cultivated in two groups: control group and BPA group (BPA30 µM). The cultures were analyzed at T0 and after 7 (T7), 14 (T14) and 21 (T21) days of culture. Evaluation of gene expression was performed by real-time PCR (RT-PCR), with the evaluated genes being: Smc1β, Sycp1 (pairing-synapsis), Spo11, Rpa, H2ax, Mlh1 and Blm [double-strand break (DSBs) generation, signaling and repair], Erα, Erβ and Errγ (estrogen receptors), Stra8 and Nalp5 (markers of meiotic progression). Oocytes from ovaries cultured and treated with BPA show changes in the expression of Spo11, H2ax and Blm genes, with a significant increase from 3- to 5-fold (P≤ 0.05). Finally, Rpa, showed a 100-fold increment (P≤ 0.01). Erα, Erβ and Errγ genes showed a BPA up-regulation of 2-4-fold in all of the culture times (P≤ 0.05). Oocytes exposed to BPA showed an up-regulation of genes involved in DSB generation, signaling and repair except by Mlh1. Thus, BPA can modify the gene expression pattern, which may explain the effects of BPA on female germ cells.