Abstract 11964: The Effect of Endothelin-1 on Angiotensin II-Induced Renal Injury

Abstract

Introduction: Hypertension (HT) and kidney disease is increasingly recognized as a global public health problem. Angiotensin II (AngII) induces endothelin-1 (ET-1), and ET-1 is a key mediator of kidney fibrosis. Hypothesis: Inhibition of ET-1 may contribute to modulation of HT and renal injury induced by angiotensin II. Methods: In addition to wild-type (WT) mice, we also used IL-1 receptor antagonist-deficient (IL-1Ra -/- ) mice that were prone to AngII-induced renal inflammation, because WT (C57BL) mice were genetically resistant to renal injury in response to AngII. Both mice were infused with AngII (1000ng/kg/min) using subcutaneous osmotic pumps for 14 days. Results: Systolic blood pressure in IL-1Ra -/- mice significantly increased compared with WT mice (197±5 vs 169±9 mmHg, p<0.05). Furthermore, renal preproendothelin-1 mRNA expression and serum levels of ET-1 were also significantly higher in IL-1Ra -/- mice (p<0.05). Immunostaining revealed that ET-1 was elevated in glomeruli and tubules in the cortex of IL-1Ra -/- mice compared with WT mice (Figure upper panels: ET-1 staining), indicating elevated ET-1 might contribute to glomerular injury (Figure middle panels: PAS staining) and intratubule fibrosis (Figure lower panels: Elastica Masson staining) detected in the histological analysis. Finally, we investigated whether pharmacological inhibition of ET receptors could prevent AngII-induced renal injury in IL-1Ra -/- mice. Bosentan significantly decreased AngII-induced HT, and protected renal injury in IL-1Ra -/- mice. On the other hand, treatment of hydralazine, an antihypertensive agent, did not suppress renal damage in AngII-infused IL-1Ra -/- mice in spite of improvement of HT. Conclusions: Our results indicate that inhibition of ET-1 might protect AngII-induced renal inflammation beyond an antihypertensive therapy, suggesting that we might be required to develop new strategies for blocking ET-1 to prevent hypertensive renal injury.