Blood pressure-independent renoprotective effects of small interference RNA targeting liver angiotensinogen in experimental diabetes

Cruz-Lopez, Edwyn O.1; Ren, Liwei1,2; Uijl, Estrellita1,3; Clahsen-van Groningen, Marian C.4,5; van Veghel, Richard1; Garrelds, Ingrid M.1; Domenig, Oliver6; Poglitsch, Marko6; Zlatev, Ivan7; Rooney, Timothy7; Kasper, Anne7; Nioi, Paul7; Foster, Don7; Danser, A. H. Jan1

2022-10-01

10.1111/bph.15955

BRITISH JOURNAL OF PHARMACOLOGY   Impact Factor & Quartile

0007-1188

1476-5381

Background and Purpose Small interfering RNA (siRNA) targeting liver angiotensinogen lowers blood pressure, but its effects in hypertensive diabetes are unknown. Experimental Approach To address this, TGR (mRen2)27 rats (angiotensin II-dependent hypertension model) were made diabetic with streptozotocin over 18 weeks and treated with either vehicle, angiotensinogen siRNA, the AT(1) 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.

diabetes hypertension renin-angiotensin system small interfering RNA

SCI

English

Others

Mexican National Council of Science and Technology[739513] ; National Natural Science Foundation of China[81900668] ; Shenzhen Key Medical Discipline Construction Fund[SZXK059]

Pharmacology & Pharmacy

Pharmacology & Pharmacy

WOS:000863964500001

WILEY

PHARMACOLOGY & TOXICOLOGY

Web of Science

1.Erasmus MC, Div Vasc Med & Pharmacol, Dept Internal Med, Rotterdam, Netherlands
2.Southern Univ Sci & Technol, Affiliated Hosp 1, Jinan Univ, Dept Pharm,Shenzhen Peoples Hosp,Clin Med Coll 2, Shenzhen, Peoples R China
3.Erasmus MC, Div Nephrol & Transplantat, Dept Internal Med, Rotterdam, Netherlands
4.Erasmus MC, Dept Pathol, Rotterdam, Netherlands
5.Rhein Westfal TH Aachen, Univ Hosp Aachen, Inst Expt Med & Syst Biol, Aachen, Germany
6.Attoquant Diagnost, Vienna, Austria
7.Alnylam Pharmaceut, Cambridge, MA USA

Cruz-Lopez, Edwyn O.,Ren, Liwei,Uijl, Estrellita,et al. Blood pressure-independent renoprotective effects of small interference RNA targeting liver angiotensinogen in experimental diabetes[J]. BRITISH JOURNAL OF PHARMACOLOGY,2022.

Cruz-Lopez, Edwyn O..,Ren, Liwei.,Uijl, Estrellita.,Clahsen-van Groningen, Marian C..,van Veghel, Richard.,...&Danser, A. H. Jan.(2022).Blood pressure-independent renoprotective effects of small interference RNA targeting liver angiotensinogen in experimental diabetes.BRITISH JOURNAL OF PHARMACOLOGY.

Cruz-Lopez, Edwyn O.,et al."Blood pressure-independent renoprotective effects of small interference RNA targeting liver angiotensinogen in experimental diabetes".BRITISH JOURNAL OF PHARMACOLOGY (2022).