Blood pressure-independent renoprotection in diabetic rats treated with small interfering RNA targeting liver angiotensinogen

OBJECTIVE: Small interfering RNA (siRNA) targeting liver angiotensinogen (AGT) exerts beneficial effects on blood pressure and kidney function, but its effects in diabetes are still unknown. DESIGN AND METHOD: To address this, TGR(mREN2)27 rats (a model of angiotensin II-dependent hypertension) were made diabetic with streptozotocin for 18 weeks and treated with vehicle, AGT siRNA, the angiotensin receptor blocker valsartan, the ACE inhibitor captopril, valsartan + siRNA, or valsartan + captopril for the final 3 weeks. Arterial pressure was measured via radiotelemetry. RESULTS: Baseline mean arterial pressure (MAP) was 164 ± 1 mm Hg. Diabetes resulted in albuminuria, accompanied by glomerulosclerosis and podocyte effacement, without a further rise in MAP or a change in glomerular filtration rate. All treatments lowered MAP (by ~50 mm Hg) and cardiac hypertrophy identically. Treatment with siRNA resulted in the largest reduction in AGT, while in combination with valsartan AGT virtually disappeared. Only the dual treatment groups and captopril lowered circulating angiotensin II and aldosterone. No treatment affected renal AGT mRNA expression, confirming the liver-specificity of the siRNA. Yet, siRNA with or without valsartan, and valsartan + captopril, but not valsartan alone, or captopril alone, reduced renal angiotensin I and II. All treatments lowered albuminuria and proteinuria, while only siRNA with or without valsartan improved glomerulosclerosis and podocyte dysfunction. Multiple linear regression confirmed both mean arterial pressure and renal angiotensin II as independent determinants of albuminuria. CONCLUSIONS: In conclusion, AGT siRNA exerts renoprotection in diabetic TGR(mREN2)27 rats, and this relies, at least in part, on the suppression of renal angiotensin II formation from liver-derived AGT. Consequently, AGT siRNA may prove beneficial in human diabetic kidney disease.