Submitted on June 21, 2007
Accepted on November 2, 2007
Purinergic Receptors Contribute to Early Mesangial Cell Transformation and Renal Vessel Hypertrophy during Angiotensin II-Induced Hypertension
Miguel L Graciano1*, Akira Nishiyama2, Keith E Jackson3, Dale M Seth1, Rudy M. Ortiz1, Minolfa Prieto-Carrasquero1, Hiroyuki Kobori1, and L. Gabriel Navar4
1 Department of Physiology, Tulane University School of Medicine, New Orleans, Louisiana, United States
2 Pharmacology, Kagawa Medical University, Kagawa, Japan
3 Department of Basic Pharmaceutical Sciences, University of Louisiana at Monroe, Monroe, Louisiana, United States
4 Department of Physiology, Tulane University School of Medicine, New Orleans,, Louisiana, United States
* To whom correspondence should be addressed. E-mail: miglugra{at}terra.com.br.
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 which stimulates 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 non-selective 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±0.1mm to 6.0±0.1mm in Ang II rats was also prevented by clopidogrel (4.8±0.1mm) and PPADS. Ang II infusion led to interstitial macrophage infiltration (105±16 cell/mm2 vs 62±4 cell/mm2) and tubular proliferation (71±15 vs 20±4 cell/mm2) and these effects were prevented by clopidogrel (52±4 cell/mm2 and 36±3 cell/mm2) and PPADS. RIF ATP levels were higher in Ang II infused rats than in control rats (11.8±1.9 nmol/L 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.
