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

Edwyn O. Cruz-Lopez, Liwei Ren, Estrellita Uijl, Marian C. Clahsen-van Groningen, Richard van Veghel, Ingrid M. Garrelds, Oliver Domenig, Marko Poglitsch, Ivan Zlatev, Timothy Rooney, Anne Kasper, Paul Nioi, Don Foster, A. H. Jan Danser*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

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.

Original languageEnglish
Pages (from-to)80-93
Number of pages14
JournalBritish Journal of Pharmacology
Volume180
Issue number1
DOIs
Publication statusE-pub ahead of print - 15 Sep 2022

Bibliographical note

Funding information
This work was partially supported by Alnylam Pharmaceuticals. E. O. Cruz-Lopez was supported by the Mexican National Council of Science and Technology (grant no. 739513).
L. Ren was supported by a National Natural Science Foundation of China (grant No. 81900668) and Shenzhen Key Medical Discipline Construction Fund (grant No. SZXK059).

© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society

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