AT1 receptor mediated augmentation of intrarenal angiotensinogen in angiotensin II-dependent hypertension.
Angiotensin (Ang) II-infused hypertensive rats exhibit increases in renal angiotensinogen mRNA and protein, as well as urinary angiotensinogen excretion in association with increased intrarenal Ang II content. The present study was performed to determine if the augmentation of intrarenal angiotensinogen requires activation of Ang II type 1 (AT1) receptors. Male Sprague-Dawley rats (200 to 220 g) were divided into 3 groups: sham surgery (n=10), subcutaneous infusion of Ang II (80 ng/min, n=11), and Ang II infusion plus AT1 blocker (ARB), olmesartan (5 mg/d, n=12). Ang II infusion progressively increased systolic blood pressure (SBP) compared with sham (178+/-8 mm Hg versus 119+/-4 at day 11). ARB treatment prevented hypertension (113+/-6 at day 11). Twenty-four-hour urine collections were taken at day 12, and plasma and tissue samples were harvested at day 13. The Ang II+ARB group had a significant increase in plasma Ang II compared with Ang II and sham groups (365+/-46 fmol/mL versus 76+/-9 and 45+/-14, respectively). Nevertheless, ARB treatment markedly limited the enhancement of kidney Ang II by Ang II infusion (65+/-17 fmol/g in sham, 606+/-147 in Ang II group, and 288+/-28 in Ang II+ARB group). Ang II infusion significantly increased kidney angiotensinogen compared with sham (1.69+/-0.21 densitometric units versus 1.00+/-0.17). This change was reflected by increased angiotensinogen immunostaining in proximal tubules. ARB treatment prevented this increase (1.14+/-0.12). Urinary angiotensinogen excretion rates were enhanced 4.7x in Ang II group (4.67+/-0.41 densitometric units versus 1.00+/-0.21) but ARB treatment prevented the augmentation of urinary angiotensinogen (0.96+/-0.23). These data demonstrate that augmentation of intrarenal angiotensinogen in Ang II-infused rats is AT1-dependent and provide further evidence that urinary angiotensinogen is closely linked to intrarenal Ang II in Ang II-dependent hypertension.
Kobori
Hiroyuki
H
Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, 1430 Tulane Avenue, #SL39, New Orleans, LA 70112-2699, USA. hkobori@tulane.edu
Prieto-Carrasquero
Minolfa C
MC
Ozawa
Yuri
Y
Navar
L Gabriel
LG
D000804:Angiotensin II / Q000008:administration & dosage / Q000502:physiology / Q000633:toxicity*; D047228:Angiotensin II Type 1 Receptor Blockers; D000808:Angiotensinogen / Q000096:biosynthesis* / Q000652:urine; D000818:Animals; D006973:Hypertension / Q000378:metabolism* / Q000517:prevention & control; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D000068557:Olmesartan Medoxomil; D011507:Proteinuria / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D012083:Renin / Q000097:blood; D013777:Tetrazoles / Q000494:pharmacology*
D047228:Angiotensin II Type 1 Receptor Blockers; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000808:Angiotensinogen; D000804:Angiotensin II; D000068557:Olmesartan Medoxomil; D012083:Renin