PubMed · 15754562
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Deborah Huber. 2005. Revised quality indicator.. https://pubmed.ncbi.nlm.nih.gov/15754562/
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Angiotensinogen-, angiotensin-converting enzyme-, and angiotensin II (Ang II) type 1 receptor (AT(1)R)-deficient mice exhibit a dilated renal pelvis (hydronephrosis) and a small papilla. These abnormalities have been attributed to impaired development of the ureteral and pelvic smooth muscle. Defects in the growth and branching of the ureteric bud (UB), which gives rise to the collecting system, have not been examined carefully. This study tested the hypothesis that Ang II stimulates UB growth and branching in the intact metanephros. Immunohistochemistry demonstrated that embryonic mouse kidneys express AT(1)R in the UB and its branches. Embryonic day 11.5 metanephroi were microdissected from Hoxb7-green fluorescence protein mice and grown for 48 h in serum-free medium in the presence or absence of Ang II. The number of green fluorescence protein-positive UB branch points (BP) and tips was monitored in each explant at 24 and 48 h. Ang II increased the number of UB tips and BP at 24 h (tips: 24.3 +/- 1.1 versus 18.3 +/- 0.7, P < 0.01; BP: 14.4 +/- 0.6 versus 11.7 +/- 0.6, P < 0.01) and 48 h (tips: 30.2 +/- 1.3 versus 22.9 +/- 0.8, P < 0.01; BP: 21.3 +/- 0.9 versus 15.7 +/- 0.6, P < 0.01) compared with control. In contrast, treatment of metanephroi with the AT(1)R antagonist candesartan inhibited UB branching, decreasing the number of UB tips and BP. Similarly, inhibition of EGF receptor (EGFR) tyrosine kinase activity abrogated Ang II-stimulated UB branching. A cross-talk between the renin-angiotensin system and EGFR signaling was elicited at the cellular level by the ability of Ang II to induce tyrosine phosphorylation of EGFR in UB cells and through abrogation of Ang II-induced UB cell branching using an EGFR tyrosine kinase inhibitor. These data demonstrate that Ang II, acting via the AT(1)R, stimulates UB branching morphogenesis. This process depends on tyrosine phosphorylation of the EGFR. Cooperation of AT(1)R and EGFR signaling therefore is important in the development of the renal collecting system.
BACKGROUND: To counteract the contribution of angiotensin II to shock-induced ischaemic organ damage pharmacologic blockade of the renin-angiotensin-system (RAS) is currently under investigation. To evaluate potential side-effects of RAS blockade regarding capillary leak, we studied alterations in microvascular permeability in various organs during haemorrhagic shock (HS) in rats pretreated with candesartan (AT(1)-receptor antagonism) or enalaprilat (ACE-inhibition). METHODS: Thirty-eight instrumented and anaesthetized animals received either candesartan, enalaprilat or placebo. Within each of the three groups 6-7 animals were exposed to HS and 6 animals of each group served as normovolaemic controls. After 30 min of shock, 50 mg kg(-1) Evans blue (EB) was injected i.v. followed by a distribution period of 20 min. Exsanguination was performed with saline, before harvesting organs to quantify albumin-bound EB extravasation. RESULTS: To reduce cardiac output from 37.5 (1.3) to 20.4 (1.1) ml min(-1) [mean (SEM)] in the shock groups, withdrawal of 4.0 (0.25) ml [mean (SEM)] blood was necessary. Simultaneously mean arterial pressure decreased from 77.5 (3.2) to 36.1 (2) mm Hg. Serum lactate increased significantly from 1.3 (0.1) to 3.5 (0.24) mmol litre(-1). Treatment with candesartan increased EB extravasation in the kidney in normovolaemic controls. Specific AT(1) and ACE-blockade before acute non-resuscitated HS significantly increased EB extravasation in the rat ileum by 53 and 66%, respectively. CONCLUSION: This observation of increased microvascular albumin extravasation should be borne in mind for any interventional use of candesartan or enalaprilat during circulatory stress.
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