Abstract 059: Loss of AT1 Receptors in the Podocyte Does Not Protect Against Renal Injury
Chronic kidney disease (CKD) arising from hypertension or other etiologies often progresses to ESRD despite treatment. One of the mainstays of treatment for CKD is blockade of the renin-angiotensin system (RAS). RAS blockers - angiotensin converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) - have the unique ability to decrease urine albumin excretion independent of systemic blood pressure. Despite their clinical effectiveness, RAS blockers do not completely stop CKD progression, thus there exists a need for new therapies. The association between proteinuria and an over-active RAS is well described and is mediated by angiotensin II (ang II) via the AT1 angiotensin receptor. This suggests that ang II, via AT1 receptors, promotes proteinuria and that this may be an important pathway in the pathogenesis of CKD. Yet, the mechanism and cellular site of action where ang II causes proteinuria have not been clearly demonstrated. To investigate the role of AT1 in podocytes we used cell-specific gene targeting to generate mice lacking all AT1 receptors in the podocyte (PodKOs). PodKOs were then crossed with mice expressing a renin transgene (RenTg) to generate PodKO-RenTg mice. RenTg mice are hypertensive and provide an effective genetic model in which to study RAS over-activation. We hypothesized that AT1 signaling is a critical mediator of albuminuria in hypertensive kidney disease and that actions of AT1 receptors in the podocyte mediate kidney injury. PodKO mice develop normally and there is no difference in kidney weight between Cre- and Cre+ mice (6.9 ± 0.5 mg/g BW vs 7.0 ± 0.3 mg/g BW). At baseline, there was no significant difference in albumin excretion between 24 week old RenTg and PodKO-RenTg mice (210 ± 70.9 μg vs 228.7 ± 37.6 μg). When the mice were subjected to uninephrectomy to induce CKD, both RenTg and PodKO-RenTg mice developed similar degrees of albuminuria (279.9 ± 105.8 μg vs 366.8 ± 105.9 μg). However, kidneys from PodKO-RenTg mice had higher levels of glomerulosclerosis and mesangial expansion. Taken together, these data suggest that AT1 receptors in podocytes do not promote albuminuria and may have protective effects.
Author Disclosures: S.A. Johnson: None. T. White: None. R. Griffiths: None. S.B. Gurley: None. T. Coffman: None.
- © 2015 by American Heart Association, Inc.