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Kidney and Lung ACE2 Expression After an ACE Inhibitor Or an Ang II Receptor Blocker: Implications for COVID-19

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Kidney and Lung ACE2 Expression After an ACE Inhibitor Or an Ang II Receptor Blocker: Implications for COVID-19 RESEARCH LETTERS www.jasn.org Kidney and Lung ACE2 Expression after an ACE Inhibitor or an Ang II Receptor Blocker: Implications for COVID-19 Jan Wysocki,1 Enrique Lores,1 Minghao Ye,1 Maria Jose Soler,1,2 and Daniel Batlle1 1Division of Nephrology and Hypertension, Department of Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois 2Department of Nephrology, Vall d’Hebron University Hospital, Barcelona, Spain JASN 31: 1941–1943, 2020. doi: https://doi.org/10.1681/ASN.2020050667 After the recognition early in 2020 that the effect of captopril and telmisartan, associated with a significant increase in angiotensin-converting enzyme 2 (ACE2) administered for 2 weeks, to pharmaco- cytosolic ACE2 protein (Figure 1D) sug- is the main receptor for severe acute logically inhibit ACE activity and the gesting internalization of the protein. By respiratory syndrome coronavirus 2 AT1 receptor, respectively. confocal microscopy (Figure 1C), ACE2 (SARS-CoV-2),1 concerns were rap- We also studied the effect of kidney staining was mostly apical but could also idly raised about the use of renin- ACE deficiency on kidney ACE2 expres- be seen in the cytoplasm of tubular cells angiotensin system (RAS) blockers in sion in two genetic models of kidney from captopril-treated mice which was patients with coronavirus disease 2019 ACE ablation to investigate the effect of less evident in control mice. ACE staining, (COVID-19).2–4 The concerns were kidney ACE deficiency on kidney ACE2 by contrast, remained restricted to the largely based on previous studies showing expression. Our findings in the two apical membrane (Figure 1C). that angiotensin II type 1 (AT1) receptor models of kidney ACE genetic ablation, ACE2proteinintotalkidneylysatesfrom blockers (ARBs) and ACE inhibitors can global in the ACE.4 mice (Supplemental telmisartan-treated mice was also not signif- upregulate ACE2 in certain experimental Figure1)andrestrictedtothekidney icantly different from vehicle-treated mice conditions, although results have not al- in the ACE8/8 mice (Supplemental (114%616%). However, in isolated kidney ways been consistent.3–6 Nevertheless, Figure 2), revealed that lack of ACE pro- membranes, there was a significant decrease the question is important because certain tein was associated with a significant in ACE2 protein (76%69% of the vehicle- groups of patients at risk of severe reduction of kidney ACE2 protein that treated mice; P50.03) (Figure 1B). COVID-19—including those with hyper- was not accompanied by a reduction in In lung tissue, ACE2 protein is tension, heart disease, diabetes mellitus, kidney ACE2 mRNA. low.9,10 Consistent with this, attempts and the elderly—are often treated with Kidney cortex of mice treated with to perform Western blots with either to- RAS blockers.2 captopril or telmisartan for 2 weeks tal lysates or isolated membranes did not In polarized epithelia, like the lungs, and respective vehicle-treated controls yield a signal. Therefore, our results are kidneys and intestine, ACE2 in its full- were used to evaluate ACE2 mRNA, pro- limited to ACE2 activity that, although length form is anchored to the apical tein, and activity (see methods in low, was consistently detected and can plasma membrane.7,8 Although kidneys Supplemental Appendix). No significant be considered a surrogate for relative have abundant ACE2 in the proximal changes in mRNA levels were found be- protein abundance. Neither captopril tubule, lungs have a low level of ACE2 tween captopril-treated and control nor telmisartan had a significant effect expression.9,10 However, type 2 pneu- mice (99%621% of control). ACE2 ac- mocytes express ACE2 and, moreover, tivity and protein were lower in lysates Received May 16, 2020. Accepted June 27, 2020. possess Transmembrane protease, serine from captopril-treated mice (81%68% 2 (TMPRSS2), a protease critical for and 71%65% of control mice, respec- Published online ahead of print. Publication date priming of the ACE2–SARS-CoV-2 tively) but the difference did not reach available at www.jasn.org. complex, a step needed for cell entry.1,10 statistical significance. In isolated mem- Correspondence: Dr. Daniel Batlle, Division of Ne- The effect of ACE inhibitors and ARBs branes, however, the decrease in kidney phrology and Hypertension, Department of Medicine, Northwestern University, The Feinberg School of on ACE2 protein expression in the lungs, ACE2 protein was profound and statisti- Medicine, 320 E Superior, Tarry 14-727, Chicago, IL however, has not been previously report- cally significant (37%64% of the vehicle- 60611. Email: [email protected] P5 ed. To gain insight into this question, we treated mice; 0.0004) (Figure 1A). This Copyright © 2020 by the American Society of used kidney and lung lysates to examine decrease in membrane-bound ACE2 was Nephrology JASN 31: 1941–1943, 2020 ISSN : 1046-6673/3109-1941 1941 RESEARCH LETTERS www.jasn.org A B 250 ** 250 * 200 200 150 150 100 100 50 50 % mean of the Control % mean of the Control 0 0 Control Captopril Control Telm C ACE2 ACE Merge D 250 * 200 150 Control 100 Captopril 50 % mean of the Control 0 Cytosol ACE2 protein E F 1.5 1.5 ns ns 1.0 1.0 0.5 0.5 Lung ACE2 act (RFU/ug/hr) 0.0 Lung ACE2 act (RFU/ug/hr) 0.0 Control (8) Capto (8) Control (6) Telm (6) Figure 1. ACE2 expression in kidney and lung membranes from captopril and telmisartan treated mice. (A and B) ACE2 protein in kidney membranes from (A) captopril- and (B) telmisartan-treated mice. *P,0.05; **P,0.01. (C) Confocal microscopy of kidney proximal tubule showing ACE2 (red), ACE (green), and merged image (yellow). ACE2 and ACE are mainly in the apical site in both control (upper panel) and captopril treated mice (lower panel). ACE2 staining is also seen in the cytoplasm (double arrow) of a captopril-treated mouse which is not as evident in control mice. The inset (D) (bar graphs) shows a significant increase in cytosolic ACE2 protein in cytosolic membranes from captopril treated as compared with vehicle-treated mice, *P,0.05. Data are expressed as percentage of control. (E and F) ACE2 enzymatic activity in isolated membrane preparations from lungs from (E) captopril- and (F) telmisartan-treated mice. In lungs, no significant dif- ferences were detected as compared to their respective controls. Act, activity; Telm, telmisartan. on ACE2 activity in lung total lysates protein. Within lung tissue, ACE2 pro- its full-length form is anchored to the (Supplemental Figure 3). tein is detectable only in type 2 pneumo- apical plasma membrane.7,8,10 Here we Likewise, in lung membranes, ACE2 cytes. In this cell type, Transmembrane show that captopril and telmisartan activity was unaffected by either captopril protease, serine 2 (TMPRSS2), a prote- both decrease kidney ACE2 protein in (Figure 1E) or telmisartan (Figure 1F). ase critical for activation and fusion of kidney membranes without signifi- In assessing the relative quantities of the SARS-CoV-2 and ACE2 complex, is cantly affecting protein abundance in ACE2 that can act as the SARS-CoV-2 re- also present.1,10 total kidney lysates (Figure 1). Capto- ceptor, what matters most is the abundance In polarized epithelia like in the pril, in particular, produced a marked of full-length, membrane-bound ACE2 lungs, kidneys, and intestine, ACE2 in decline in ACE2 protein in kidney 1942 JASN JASN 31: 1941–1943, 2020 www.jasn.org RESEARCH LETTERS membranes while increasing cytosolic FUNDING SARS-CoV-2 cell entry depends on ACE2 ACE2 (Figure 1). and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181: 271–280.e8, In conclusion, genetic ablation and in- D. Batlle was funded by National Institute of 2020 Diabetes and Digestive Kidney Diseases grant hibition of kidney ACE are both ac- 2. Fang L, Karakiulakis G, Roth M: Are patients RO1DK104785. companied by a reduction of kidney with hypertension and diabetes mellitus at ACE2 expression. This suggests changes increased risk for COVID-19 infection? [pub- intheexpressioninoneenzymemayelicit lished correction appears in Lancet Respir Med 8: e54, 2020]. Lancet Respir Med 8: e21, similarly directional changes in the ACKNOWLEDGMENTS other homolog such that formation 2020 3. Danser AJ, Epstein M, Batlle D: Renin- and degradation of angiotensin II can This work was supported by the Joseph and angiotensin system blockers and the be regulated. The administration of an Bessie Feinberg Foundation (Dr. Daniel COVID-19 pandemic: At present there is no ACE inhibitor, captopril, and an ARB, tel- Batlle). We thank Dr. Hong D. Xiao (Provi- evidence to abandon renin-angiotensin sys- – misartan, decreased ACE2 protein expres- dence Portland Medical Center, Portland, tem blockers. Hypertension 75: 1382 1385, 2020 sion in kidney-isolated membranes. Each OR)andDr.KennethE.Bernstein(Cedars type of RAS blocker had no detectable ef- 4. Vaduganathan M, Vardeny O, Michel T, Sinai, Los Angeles, CA) for generously pro- McMurray JJV, Pfeffer MA, Solomon SD: fect on ACE2 activity in lung-isolated viding kidneys from ACE deficiency models. – – fi Renin angiotensin aldosterone system in- membranes. These ndings altogether Dr. Daniel Batlle reports nonfinancial sup- hibitors in patients with Covid-19. NEngl show that ACE2 is not increased in two port from Angiotensin Therapeutics Inc., JMed382: 1653–1659, 2020 organs that are potential target sites for outside the submitted work. Dr. Maria Jose 5. Soler MJ, Ye M, Wysocki J, William J, SARS-CoV-2 infection. In fact, in kidney Lloveras J, Batlle D: Localization of ACE2 in Soler reports personal fees from AstraZeneca, fi apical membranes, ACE2 protein is de- fi the renal vasculature: Ampli cation by an- non nancial support from Boehringer In- giotensin II type 1 receptor blockade using creased after both captopril and telmisartan fi gelheim, non nancial support from Eli Lilly, telmisartan.
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