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Renoprotective Effects of Small Interfering RNA Targeting Liver Angiotensinogen in Experimental Chronic Kidney Disease

Publication Details

Hypertension

March 2021

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Author(s)

Dominique M Bovée^{1 2}, Liwei Ren^{1 3}, Estrellita Uijl^{1 2}, Marian C Clahsen-van Groningen⁴, Richard van Veghel¹, Ingrid M Garrelds¹, Oliver Domenig⁵, Marko Poglitsch⁵, Ivan Zlatev⁶, Jae B Kim⁶, Stephen Huang⁶, Lauren Melton⁶, Xifeng Lu⁷, Ewout J Hoorn², Don Foster⁶, A H Jan Danser¹

Affiliations

¹Division of Vascular Medicine and Pharmacology (D.M.B., L.R., E.U., R.v.V., I.M.G., A.H.J.D.), Erasmus MC, University Medical Center Rotterdam, the Netherlands; ²Division of Nephrology and Transplantation, Department of Internal Medicine (D.M.B., E.U., E.J.H.), Erasmus MC, University Medical Center Rotterdam, the Netherlands; ³Translational Medicine Collaborative Innovation Center, The Second Clinical Medical College (Shenzhen People's Hospital) of Jinan University, China (L.R.); 4Department of Pathology (M.C.C.-v.G.), Erasmus MC, University Medical Center Rotterdam, the Netherlands; ⁵Attoquant Diagnostics, Vienna, Austria (O.D., M.P.); ⁶Alnylam Pharmaceuticals, Cambridge, MA (I.Z., J.B.K., S.H., L.M., D.F.); ⁷Department of Physiology, AstraZeneca-Shenzhen University Joint Institute of Nephrology, Shenzhen University Health Science Center, Shenzhen University, China (X.L.)

Abstract

Small interfering RNA (siRNA) targeting liver angiotensinogen (AGT) lowers blood pressure, but its effectiveness in hypertensive chronic kidney disease is unknown. Considering that the kidney may generate its own AGT, we assessed the effectiveness of liver-targeted AGT siRNA in the 5/6th Nx (5/6th nephrectomy) rat—a hypertensive chronic kidney disease model. Five weeks after 5/6th Nx (baseline), rats were subjected to vehicle, AGT siRNA, AGT siRNA+losartan, losartan, or losartan+captopril. Baseline mean arterial pressure was 160±6 mm Hg. Over the course of 4 weeks, mean arterial pressure increased further by ≈15 mm Hg during vehicle treatment. This rise was prevented by AGT siRNA. Losartan reduced mean arterial pressure by 37±6 mm Hg and increased plasma Ang (angiotensin) II. Both AGT siRNA and captopril suppressed these effects of losartan, suggesting that its blood pressure–lowering effect relied on stimulation of vasodilator Ang II type 2 receptors by high Ang II levels. Proteinuria and cardiac hypertrophy increased with vehicle, and these increases were comparably abrogated by all treatments. No intervention improved glomerular filtration rate, while siRNA and losartan equally diminished glomerulosclerosis. AGT siRNA±losartan reduced plasma AGT by >95%, and this was accompanied by almost complete elimination of Ang II in kidney and heart, without decreasing renal AGT mRNA. Multiple linear regression confirmed both mean arterial pressure and renal Ang II as independent determinants of proteinuria. In conclusion, AGT siRNA exerts renoprotection in the 5/6th Nx model in a blood pressure–independent manner. This relies on the suppression of renal Ang II formation from liver-derived AGT. Consequently, AGT siRNA may prove beneficial in human chronic kidney disease.