Ali Hassan

Ying Tian, Ali Hassan, Wei Zheng, Darren Roesch, Kathryn Sandberg & Joseph G. Verbalis

Department of Medicine, Georgetown University, 4000 Reservoir Road, NW, Washington, DC 20007.

Renal escape from vasopressin (AVP) is an important adaptive mechanism to maintain water balance during inappropriate AVP secretion. Renal escape is accompanied by down-regulation of renal aquaporin-2 (AQP2) and AVP V2 receptor (V2R) expression. However, quantitative ascertainment of the causal relation between V2R expression and AQP2-mediated urine concentration is difficult because of the presence of ‘spare’ V2 receptors in kidney collecting duct cells. To evaluate the functional impact of reduced V2R expression, we synthesized a 21-bp siRNA targeted to V2R that decreased V2R B_max by ˜50% 48h after administration in vivo (Hassan, et al., EB2004 Abstracts). C57B6 mice were infused with dDAVP (0.25 ng/h) for 3d to produce maximal antidiuresis, and then were injected with either the V2R-targeting siRNA or a control construct. On day 2 after treatment, 24h urine volume was significantly increased (1.07 ± 0.07 vs. 0.69 ± 0.08 ml, p<0.01) and urine osmolality was significantly decreased (3,310 ± 94 vs. 4,133 ± 313 mOsm/kg H2O, p<0.01) in siRNA-treated mice (n=10) compared to controls (n=7). These data indicate that siRNA methodology can be utilized in vivo to reduce expression of kidney V2R to a sufficient degree to cause functional impairments in maximal antidiuresis. This approach can therefore be used to delineate the relation between V2R expression and AQP2-mediated urine concentration.

Experimental Biology 2004, Washington, DC, Abstract 7651, 2004.