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

Dominique M. Bovée; Liwei Ren; Estrellita Uijl; Marian C. Clahsen-Van Groningen; Richard Van Veghel; Ingrid M. Garrelds; Oliver Domenig; Marko Poglitsch; Ivan Zlatev; Jae B. Kim; Stephen Huang; Lauren Melton; Xifeng Lu; Ewout J. Hoorn; Don Foster; A. H.Jan Danser

doi:10.1161/HYPERTENSIONAHA.120.16876

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

Dominique M. Bovée, Liwei Ren, Estrellita Uijl, Marian C. Clahsen-Van Groningen, Richard Van Veghel, Ingrid M. Garrelds, Oliver Domenig, Marko Poglitsch, Ivan Zlatev, Jae B. Kim, Stephen Huang, Lauren Melton, Xifeng Lu, Ewout J. Hoorn, Don Foster, A. H.Jan Danser^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	16876
Pages (from-to)	1600-1612
Number of pages	13
Journal	Hypertension
Volume	77
Issue number	5
DOIs	https://doi.org/10.1161/HYPERTENSIONAHA.120.16876
Publication status	Published - 1 May 2021

Bibliographical note

Funding Information:
This work was partially supported by Alnylam Pharmaceuticals. D.M. Bovée and E.J. Hoorn were supported by the Dutch Kidney Foundation (KSP-14OK19). L. Ren was supported by a National Natural Science Foundation of China grant No. 81900668. X. Lu was supported by the National Natural Science Foundation of China (grant No. 81870605), the Shenzhen Key Laboratory of Metabolism and Cardiovascular Homeostasis (grant No. ZDSYS20190902092903237), and the Shenzhen Municipal Science and Technology Innovation Council (grant No. JCYJ20190808170401660).

Publisher Copyright:
© 2021 American Heart Association, Inc.

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Bovée, D. M., Ren, L., Uijl, E., Clahsen-Van Groningen, M. C., Van Veghel, R., Garrelds, I. M., Domenig, O., Poglitsch, M., Zlatev, I., Kim, J. B., Huang, S., Melton, L., Lu, X., Hoorn, E. J., Foster, D., & Danser, A. H. J. (2021). Renoprotective Effects of Small Interfering RNA Targeting Liver Angiotensinogen in Experimental Chronic Kidney Disease. Hypertension, 77(5), 1600-1612. Article 16876. https://doi.org/10.1161/HYPERTENSIONAHA.120.16876

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title = "Renoprotective Effects of Small Interfering RNA Targeting Liver Angiotensinogen in Experimental Chronic Kidney Disease",

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.",

author = "Bov{\'e}e, {Dominique M.} and Liwei Ren and Estrellita Uijl and {Clahsen-Van Groningen}, {Marian C.} and {Van Veghel}, Richard and Garrelds, {Ingrid M.} and Oliver Domenig and Marko Poglitsch and Ivan Zlatev and Kim, {Jae B.} and Stephen Huang and Lauren Melton and Xifeng Lu and Hoorn, {Ewout J.} and Don Foster and Danser, {A. H.Jan}",

note = "Funding Information: This work was partially supported by Alnylam Pharmaceuticals. D.M. Bov{\'e}e and E.J. Hoorn were supported by the Dutch Kidney Foundation (KSP-14OK19). L. Ren was supported by a National Natural Science Foundation of China grant No. 81900668. X. Lu was supported by the National Natural Science Foundation of China (grant No. 81870605), the Shenzhen Key Laboratory of Metabolism and Cardiovascular Homeostasis (grant No. ZDSYS20190902092903237), and the Shenzhen Municipal Science and Technology Innovation Council (grant No. JCYJ20190808170401660). Publisher Copyright: {\textcopyright} 2021 American Heart Association, Inc.",

year = "2021",

month = may,

day = "1",

doi = "10.1161/HYPERTENSIONAHA.120.16876",

language = "English",

volume = "77",

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Bovée, DM, Ren, L, Uijl, E, Clahsen-Van Groningen, MC , Van Veghel, R , Garrelds, IM, Domenig, O, Poglitsch, M, Zlatev, I, Kim, JB, Huang, S, Melton, L, Lu, X, Hoorn, EJ, Foster, D & Danser, AHJ 2021, 'Renoprotective Effects of Small Interfering RNA Targeting Liver Angiotensinogen in Experimental Chronic Kidney Disease', Hypertension, vol. 77, no. 5, 16876, pp. 1600-1612. https://doi.org/10.1161/HYPERTENSIONAHA.120.16876

TY - JOUR

T1 - Renoprotective Effects of Small Interfering RNA Targeting Liver Angiotensinogen in Experimental Chronic Kidney Disease

AU - Bovée, Dominique M.

AU - Ren, Liwei

AU - Uijl, Estrellita

AU - Clahsen-Van Groningen, Marian C.

AU - Van Veghel, Richard

AU - Garrelds, Ingrid M.

AU - Domenig, Oliver

AU - Poglitsch, Marko

AU - Zlatev, Ivan

AU - Kim, Jae B.

AU - Huang, Stephen

AU - Melton, Lauren

AU - Lu, Xifeng

AU - Hoorn, Ewout J.

AU - Foster, Don

AU - Danser, A. H.Jan

N1 - Funding Information: This work was partially supported by Alnylam Pharmaceuticals. D.M. Bovée and E.J. Hoorn were supported by the Dutch Kidney Foundation (KSP-14OK19). L. Ren was supported by a National Natural Science Foundation of China grant No. 81900668. X. Lu was supported by the National Natural Science Foundation of China (grant No. 81870605), the Shenzhen Key Laboratory of Metabolism and Cardiovascular Homeostasis (grant No. ZDSYS20190902092903237), and the Shenzhen Municipal Science and Technology Innovation Council (grant No. JCYJ20190808170401660). Publisher Copyright: © 2021 American Heart Association, Inc.

PY - 2021/5/1

Y1 - 2021/5/1

N2 - 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.

AB - 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.

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JF - Hypertension

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ER -

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

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