Full text
| |
| Author(s): |
Flavia Leticia Martins
Total Authors: 1
|
| Document type: | Master's Dissertation |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) |
| Defense date: | 2019-07-25 |
| Examining board members: |
Adriana Castello Costa Girardi;
Antonio Carlos Seguro
|
| Advisor: | Adriana Castello Costa Girardi |
| Abstract | |
Glucagon-Like Peptide is an incretin hormone evolved primarily in the glucose homeostasis. In pharmacology concentrations, this peptides shows extraglycemic actions, including diuresis, natriuresis, and anti-hypertensive effects in both patients and experimental models of arterial hypertension associated or not with diabetes. Over the last few years, our research group has demonstrated that the pharmacological actions of GLP-1, as well as other GLP-1 agonist receptors (GLP-1R), such as exenatide, are mediated, in part, by the inhibition of sodium reabsorption from activation of the isoform 3-sodium and hydrogen exchanger (NHE3) in the proximal tubule (PT). Additionally, we demonstrated that acute blockade of endogenous signalization of GLP- 1 in Wistar rats, through GLP-1R antagonist administration (exendin-9) promotes antinatriuretic and anti-diuretic outcomes, suggesting that endogenous GLP-1 exerts modulatory effect by the sodium and water reabsorption. These renal effects are mediated by alterations in the Glomerular Filtration Rate (GFR), in the same way as low phosphorylation levels of serine 552 residues of NHE3 in PT with consequent increases in NHE3-dependent sodium reabsorption. Although, the effects of the long-term blockade of GLP-1R and its possible implications on sodium reabsorption in PT and also maybe, on blood-arterial pressure (BP) remain unknown. Given the above, this study aims to test the hypothesis that endogenous GLP-1 exerts modulatory influences on arterial pressure levels and also intends to investigate possible adjacent mechanisms. For that, GLP-1R antagonist, exendin-9 (75 Micro g/rat/day), GLP-1 agonist, exenatide (10 Micro g/rat/day) or saline was administered intraperitoneally in 5-weeks age hypertensive (SHR) and also, normotensive (Wistar) rats during four weeks. Ethics Committee: 915/2017 (SHR), 042/17 (Wistar). Weekly, the indirect BP was performed through tailplethysmography We also measured direct BP through the carotid-canulation method in the last week of treatment To evaluate the urinary angiotensinogen (AGT) excretion, we performed the enzyme-linked immunosorbent assay (ELISA), and we used Western Blotting (WB) to assess protein expression. We found from the indirect measurement of BP that treatment with exendin-9 raised blood pressure levels of SHR (199 ± 4 vs. 190 ± 1 mmHg, p < 0.05) and Wistar (140 ± 4 vs. 124 ± 0.2 mmHg, p < 0.05) when compared to the control, whereas exenatide treatment demonstrated attenuation of BP elevation only in SHR rats (178 ± 1 vs. 190 ± 1 mmHg, p < 0.05). Similar results were observed in the direct measurement of BP, in which systolic blood pressure in SHR (149 ± 1 vs. 139 ± 3 mmHg, p < 0.05) and Wistar (116 ± 5 vs. 101 ± 1 mmHg, p < 0.05) was increased by exendin-9 treatment, compared to control, whereas exenatide treatment demonstrated attenuation of BP increase only in SHR rats (127 ± 1 vs. 139 ± 3 mmHg, p < 0.05). The increasing in BP in exendin-9 treatment in SHR followed lower levels of NHE3- phosphorylation (60 ± 5 vs. 100 ± 5 %SHR-Ctrl, p < 0.01) and Wistar (81 ± 5 vs. 100 ± 4 %Wistar-Ctrl, p < 0.05), suggesting an increase in this exchanger activity with higher sodium reabsorption in PT. On the other hand, the exenatide showed higher levels of NHE3 phosphorylation only in SHR rats (114 ± 7 vs. 100 ± 5 %SHR-Ctrl, p < 0.05). We also observed increases in AGT-urinary excretion in SHR (102 ± 9 vs. 47 ± 7 ng/mg, p < 0.05) and Wistar (16 ± 2 vs. 4 ± 1 ng/mg, p < 0.05), indicating activation of the renal Renin-Angiotensin System (RAS). In contrast, the exenatide proportioned decreasing in AGT-urinary excretion only in SHR rats. Thus, we conclude that the long-term blockade of GLP-1R intensifies the increasing in BP in SHR rats and also elevates BP levels in Wistar rats. This effect was associated with higher sodium reabsorption in PT by NHE3, and intrarenal RAS activation in both lineages (AU) | |
| FAPESP's process: | 17/13104-0 - Role of glucagon-like peptide-1 in the pathophysiology of hypertension |
| Grantee: | Flavia Leticia Martins |
| Support Opportunities: | Scholarships in Brazil - Master |