Abstract 383: Candesartan, in a Dose-Related Manner, Upregulates the Protective Axis of the Renal Renin Angiotensin System and Prevents Progression of Diabetic Nephropathy in db/db Mice.

Abstract

The renin-angiotensin system (RAS) plays a pivotal role in the pathophysiology of cardiovascular and kidney disease. Protection against kidney injury has been evidenced by high dose angiotensin II (Ang II) type 1 receptor (AT1R) blockers. In this study we sought to determine whether a high dose of candesartan has renoprotective actions associated with the modulation of RAS component expression in type 2 diabetic db/db mice. Systolic blood pressure (SBP), urinary albumin excretion (albumin/creatinine, ACR), and protein expression/activity of RAS components were assessed in db/db and control non-diabetic db/+ mice infused with the AT1R blocker candesartan (1, 5, 25, 75 mg/kg/day, sc, 4 weeks). Vehicle treated db/db mice exhibited increased albuminuria (38.9 ± 11.9 ACR) compared with db/+ mice (6.77 ± 1.7 ACR) with no differences in SBP between the two groups (110 ± 9 vs 116 ± 4 mmHg). Candesartan (1 mg/kg/day) had no effect on SBP, although albuminuria was decreased in db/db mice (8.8 ± 3.0 ACR). Candesartan 5 mg/kg/day reduced SBP only in db/+ mice (92 ± 8 mmHg). Diabetic mice receiving 5mg/kg/day showed less albuminuria compared with vehicle treated db/db mice (21.4 ± 6 ACR). Candesartan 25mg/kg/day reduced SBP in both db/db and db/+ mice (77 ± 5 and 76 ± 4 mmHg) and decreased albuminuria in db/db mice (14.95 ± 6.4 ACR). Reduction in SBP (80 ± 7 mmHg) with no improvement of albuminuria (55.9 ± 6 mmHg) was observed in diabetic mice receiving 75 mg/kg/day candesartan. Histological findings showed that candesartan at low dose, but not at high dose, prevented tubular damage in db/db mice. Candesartan, 1-25 mg/kg/day, increased renal expression of AT2R in db/db mice. Expression of ACE2 and MAS receptor was increased only by candesartan (1 mg) in db/db mice. ACE activity was reduced in plasma and kidney cortex of db/db mice, without effect of candesartan. ACE2 activity was increased by candesartan in plasma (5 mg/kg/day) and kidney cortex (1 mg/kg/day) from db/db mice. These results indicate that low to intermediate doses of candesartan reduce the magnitude of albuminuria and tubular damage in diabetic nephropathy. These effects were not evidenced at a higher dose of candesartan. Such processes may be due to activation of the protective axis (ACE2/MAS/AT2R) of the renal RAS.