Small interfering RNA targeting liver angiotensinogen lowered circulating angiotensinogen by >99% and uniquely restored podocyte foot processes and reduced glomerulosclerosis in diabetic rats.
Does siRNA targeting liver angiotensinogen improve blood pressure and renal outcomes in diabetic TGR (mRen2)27 rats?
siRNA targeting liver angiotensinogen provides blood pressure-independent renoprotection in a rat model of hypertensive diabetes.
BACKGROUND AND PURPOSE: Small interfering RNA (siRNA) targeting liver angiotensinogen lowers blood pressure, but its effects in hypertensive diabetes are unknown. EXPERIMENTAL APPROACH: antagonist valsartan, the ACE inhibitor captopril, valsartan + siRNA or valsartan + captopril for the final 3 weeks. Mean arterial pressure (MAP) was measured via radiotelemetry. KEY RESULTS: MAP before treatment was 153 ± 2 mmHg. Diabetes resulted in albuminuria, accompanied by glomerulosclerosis and podocyte effacement, without a change in glomerular filtration rate. All treatments lowered MAP and cardiac hypertrophy, and the largest drop in MAP was observed with siRNA + valsartan. Treatment with siRNA lowered circulating angiotensinogen by >99%, and the lowest circulating angiotensin II and aldosterone levels occurred in the dual treatment groups. Angiotensinogen siRNA did not affect renal angiotensinogen mRNA expression, confirming its liver-specificity. Furthermore, only siRNA with or without valsartan lowered renal angiotensin I. All treatments lowered renal angiotensin II and the reduction was largest (>95%) in the siRNA + valsartan group. All treatments identically lowered albuminuria, whereas only siRNA with or without valsartan restored podocyte foot processes and reduced glomerulosclerosis. CONCLUSION AND IMPLICATIONS: Angiotensinogen 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 angiotensinogen. Clinical trials should now address whether this is also beneficial in human diabetic kidney disease.
Cruz‐López et al. (Thu,) conducted a other in Hypertensive diabetes. Small interfering RNA (siRNA) targeting liver angiotensinogen vs. Valsartan, captopril, valsartan + siRNA, or valsartan + captopril was evaluated on Mean arterial pressure, albuminuria, glomerulosclerosis, and podocyte effacement. Small interfering RNA targeting liver angiotensinogen lowered circulating angiotensinogen by >99% and uniquely restored podocyte foot processes and reduced glomerulosclerosis in diabetic rats.