Purinergic receptors contribute to early mesangial cell transformation and renal vessel hypertrophy during angiotensin II-induced hypertension.
Chronic ANG II infusions lead to increases in intrarenal ANG II levels, hypertension, and tissue injury. Increased blood pressure also elicits increases in renal interstitial fluid (RIF) ATP concentrations that stimulate cell proliferation. We evaluated the contribution of purinergic receptor activation to ANG II-induced renal injury in rats by treating with clopidogrel, a P2Y12 receptor blocker, or with PPADS, a nonselective P2 receptor blocker. alpha-Actin expression in mesangial cells, afferent arteriolar wall thickness (AAWT), cortical cell proliferation, and macrophage infiltration were used as early markers of renal injury. Clopidogrel and PPADS did not alter blood pressure, renin or kidney ANG II content. alpha-Actin expression increased from control of 0.6 +/- 0.4% of mesangial area to 6.3 +/- 1.9% in ANG II-infused rats and this response was prevented by clopidogrel (0.4 +/- 0.2%) and PPADS. The increase in AAWT from 4.7 +/- 0.1 to 6.0 +/- 0.1 mm in ANG II rats was also prevented by clopidogrel (4.8 +/- 0.1 mm) and PPADS. ANG II infusion led to interstitial macrophage infiltration (105 +/- 16 vs. 62 +/- 4 cell/mm(2)) and tubular proliferation (71 +/- 15 vs. 20 +/- 4 cell/mm(2)) and these effects were prevented by clopidogrel (52 +/- 4 and 36 +/- 3 cell/mm(2)) and PPADS. RIF ATP levels were higher in ANG II-infused rats than in control rats (11.8 +/- 1.9 vs. 5.6 +/- 0.6 nmol/l, P < 0.05). The results suggest that activation of vascular and glomerular purinergic P2 receptors may contribute to the mesangial cell transformation, renal inflammation, and vascular hypertrophy observed in ANG II-dependent hypertension.
Graciano
Miguel L
ML
Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, USA. miglugra@terra.com.br
Nishiyama
Akira
A
Jackson
Keith
K
Seth
Dale M
DM
Ortiz
Rudy M
RM
Prieto-Carrasquero
Minolfa C
MC
Kobori
Hiroyuki
H
Navar
L Gabriel
LG
D000199:Actins / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000473:pathology*; D001794:Blood Pressure / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000077144:Clopidogrel; D004195:Disease Models, Animal; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D006984:Hypertrophy; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D050527:Mesangial Cells / Q000378:metabolism* / Q000473:pathology*; D058914:Purinergic Antagonists; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011983:Receptors, Purinergic / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12; D012083:Renin / Q000097:blood; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology
D000199:Actins; D008565:Membrane Proteins; C553058:P2ry12 protein, rat; D058914:Purinergic Antagonists; D058919:Purinergic P2 Receptor Antagonists; D011983:Receptors, Purinergic; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D000804:Angiotensin II; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D011732:Pyridoxal Phosphate; D000255:Adenosine Triphosphate; D000077144:Clopidogrel; D012083:Renin; D013988:Ticlopidine