Christine Perregaux

Transcytosis of the polymeric Ig receptor requires phosphorylation of serine 664 in the absence but not the presence of dimeric IgA

MDCK cells expressing the polymeric immunoglobulin (poly-Ig) receptor, cocultured with IgA-producing hybridoma cells, transported dimeric IgA (dIgA) from the basolateral into the lumenal compartment, where it was recovered as secretory component-dIgA complexes. The tail of the receptor was phosphorylated on serines 664 and 726. Each serine was mutated to alanine. Appearance of A726 receptor at the basolateral surface was reduced approximately 5-fold. This was accompanied by a approximately 5-fold reduction in dIgA transcytosis. Basolateral delivery of receptor was not affected by mutation A664, and in the absence of dIgA, the receptor accumulated in recycling basolateral endosomes. In coculture, however, dIgA transcytosis by A664 receptor was normal. Thus, entry of receptor into the transcytotic pathway requires Ser-664 phosphorylation only in the absence of dIgA.

Calcium-sensing receptors modulate renin release in vivo and in vitro in the rat.

Objectives Calcium-sensing receptors (CaSRs) have been localized in the juxtaglomerular apparatus where they may contribute to the regulation of renin release. In the present study, we investigated the in-vitro and in-vivo effects of the calcimimetic R-568 on renin release. Methods In vitro, the effect of calcimimetics on renin release was assessed by incubating freshly isolated rat juxtaglomerular cells with or without R-568 (1 and 10 μmol/l) in serum-free medium in the presence or absence of forskolin or CaCl2. In vivo, we measured the impact of R-568 (20 ng/min intravenously) on the acute changes in plasma renin activity (PRA) induced by either a 90 min infusion of the angiotensin-converting enzyme inhibitor captopril, or the β-receptor agonist isoproterenol, or of a vehicle in or after a furosemide challenge in conscious Wistar rats. Results In vitro, R-568 dose-dependently blunted renin release, but also reduced the increase in renin due to forskolin (P < 0.01). Both isoproterenol and enalapril increased in vivo PRA to 3.1 ± 0.3 and 3.7 ± 0.5 ng Ang I/ml per h, respectively (P < 0.01), compared with vehicle (1.5 ± 0.2 ng Ang I/ml per h). R-568 significantly reduced PRA to 2.1 ± 0.1 ng/ml per h in isoproterenol-treated rats and to 1.6 ± 0.2 ng/ml per h in enalapril-treated rats (P < 0.05). In low-salt treated animals, acute infusion of furosemide increased PRA from 8.7 ± 3.2 to 18.6 ± 2.3, whereas R-568 partially blunted this rise to 11.2 ± 1.5 (P = 0.02). In vivo, R-568 significantly lowered serum calcium and PTH1–84, but the drug-induced changes in PRA were independent of the changes in calcium and parathyroid hormone. Conclusion After the recent discovery of CaSRs in juxtaglomerular cells of mice, our results confirm the presence of such receptors in rats and demonstrate that these receptors modulate renin release both in vitro and in vivo. This suggests that CaSRs play a role as a regulatory pathway of renin release.

Neuroendocrine characterization and anorexigenic effects of telmisartan in diet- and glitazone-induced weight gain

Telmisartan is an angiotensin II receptor blocker with peroxisome proliferator-activated receptor-gamma agonistic properties. Telmisartan prevents weight gain and decreases food intake in models of obesity and in glitazone-treated rodents. This study further investigates the influence of telmisartan and pioglitazone and their association on weight gain and body composition by examining their influence on neuroendocrine mediators involved in food intake. Male C57/Black 6 mice were fed a high-fat diet, weight matched, and randomized in 4 treatment groups: vehicle, pioglitazone, telmisartan, and pioglitazone-telmisartan. Weight gain, food and water intake, body composition, plasma leptin levels, and the hypothalamic expression of neuroendocrine mediators were analyzed. Additional studies were performed with irbesartan and in angiotensin II 1(A) receptor-knockout mice. Telmisartan abolished weight and fat gain in vehicle- and pioglitazone-treated mice while decreasing food intake, the hypothalamic expression of the agouti-related protein, and plasma leptin levels. Modifications in neuropeptide Y and proopiomelanocortin were not consistent with changes in food intake. The effects on weight gain and expression of the agouti-related protein were intermediate with irbesartan. The effects of telmisartan on weight gain were even more pronounced in angiotensin II 1(A) receptor-knockout mice. This study confirms the anorexigenic effects of telmisartan in mice fed a high-fat diet and suggests for the first time a functional role of telmisartan on hypothalamic orexigenic agouti-related protein regulation. These anorexigenic properties abolish both weight gain and body composition modifications in fat-fed and glitazone-treated mice. The anorexigenic properties are independent from the angiotensin II 1(A) receptor.

Role of Transepithelial Transport in Triggering a Mucosal Immune Response and in Delivery of Mucosal Antibodies into Secretions

Many pathogens, including viruses, bacteria and parasites as well as toxins and allergens, gain entry into the organism by crossing the epithelia of the digestive, respiratory or genital tracts. Mucosal surfaces are protected against environmental pathogens by non immune and immune mechanisms (Mayrhofer, 1984). A distinct “mucosal” immune system plays a major role in protection, and an important component of this protection is production of secretory antibodies of the IgA isotype (slgA) (Russel and Mestecky, 1988).

P-537: Pioglitazone blunts the blood pressure response to angiotensin II in insulin-resistant zucker rats

of hypertensive vascular lesions is not yet clear, especially in obesity induced hypertension. To assess the role of adhesion molecules in that mechanism, the relationship between carotid intima-media thickness (IMT) as hypertensive vascular lesions and plasma levels of soluble adhesion molecules such as E-selectin, VCAM-1,and ICAM-1 was statistically analyzed. Carotid IMT was measured by B-mode ultrasonography and plasma levels of adhesion molecules were by ELISA method. Four hundred and sixty one subjects who underwent annual health checkups at our center were enrolled in this study. VCAM-1 was significantly correlated with blood pressure (BP)(p 0.05), and body mass index (BMI)(p 0.01). There were no correlations between ICAM-1 and BP nor BMI. E-selectin and VCAM-1 were significantly increased with BP (p 0.001), and BMI (p 0.001). Carotid IMT was significantly correlated with E-selectin. E-selectin and VCAM-1 were significantly increased with BP, and E-selectin was also significantly increased with BMI. There was no cross reaction between BP and BMI. In conclusion, E-selectin and VCAM-1 may play an important role in the pathogenesis of hypertensive vascular lesions, and E-selectin may be a key factor for obesity induced hypertensive vascular lesions.