Mesangial AT1/B2 receptor heterodimers contribute to angiotensin II hyperresponsiveness in experimental hypertension.
Angiotensin II plays a central role in the pathogenesis of hypertension and of related cardiovascular disorders by binding to and activating angiotensin II receptors (AT1 receptors). Sensitization to the vasopressor response of angiotensin II is a key feature in many cardiovascular disorders. However, underlying mechanisms responsible for angiotensin II hypersensitivity are barely understood. Because angiotensin II responsiveness of AT1 receptors can be specifically modified by AT1/B2 receptor dimerization, we determined the AT1 receptor dimerization status in an experimental model of hypertension. AT1/B2 receptor heterodimers were abundant on renal mesangial cells isolated from spontaneously hypertensive rats compared with that on cells from normotensive controls. Heterodimerization of AT1 with B2 receptors was correlated with high levels of B2 receptor protein on kidneys and on mesangial cells of hypertensive rats, as determined in immunoblot with receptor-specific antibodies. Specific inhibition of AT1/B2 receptor heterodimers revealed that these receptor heterodimers mediated an enhanced angiotensin II-stimulated Galphaq/11 activation and an increased endothelin-1 secretion of mesangial cells from hypertensive rats. Thus, AT1/B2 receptor heterodimerization contributes to angiotensin II hyperresponsiveness of mesangial cells in experimental hypertension.
AbdAlla
Said
S
Heinrich-Pette-Institut, D-20251 Hamburg, Germany.
Abdel-Baset
Ahmed
A
Lother
Heinz
H
el Massiery
Adel
A
Quitterer
Ursula
U
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D019281:Dimerization; D005920:Glomerular Mesangium / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D044140:Receptor, Angiotensin, Type 1; D043782:Receptor, Bradykinin B2; D000804:Angiotensin II