Human intestine luminal ACE2 and amino acid transporter expression increased by ACE-inhibitors

Abstract

Sodium-dependent neutral amino acid transporter B(0)AT1 (SLC6A19) and imino acid (proline) transporter SIT1 (SLC6A20) are expressed at the luminal membrane of small intestine enterocytes and proximal tubule kidney cells where they exert key functions for amino acid (re)absorption as documented by their role in Hartnup disorder and iminoglycinuria, respectively. Expression of B(0)AT1 was shown in rodent intestine to depend on the presence of the carboxypeptidase angiotensin-converting enzyme 2 (ACE2). This enzyme belongs to the renin-angiotensin system and its expression is induced by treatment with ACE-inhibitors (ACEIs) or angiotensin II AT1 receptor blockers (ARBs) in many rodent tissues. We show here in the Xenopus laevis oocyte expression system that human ACE2 also functionally interacts with SIT1. To investigate in human intestine the potential effect of ACEIs or ARBs on ACE2, we analysed intestinal biopsies taken during routine gastroduodenoscopy and ileocolonoscopy from 46 patients of which 9 were under ACEI and 13 ARB treatment. Analysis of transcript expression by real-time PCR and of proteins by immunofluorescence showed a co-localization of SIT1 and B(0)AT1 with ACE2 in the brush-border membrane of human small intestine enterocytes and a distinct axial expression pattern of the tested gene products along the intestine. Patients treated with ACEIs displayed in comparison with untreated controls increased intestinal mRNA levels of ACE2, peptide transporter PEPT1 (SLC15A1) and AA transporters B(0)AT1 and PAT1 (SLC36A1). This study unravels in human intestine the localization and distribution of intestinal transporters involved in amino acid absorption and suggests that ACEIs impact on their expression. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

Effects of Angiotensin II Receptor Blockers and ACE (Angiotensin-Converting Enzyme) Inhibitors on Virus Infection, Inflammatory Status, and Clinical Outcomes in Patients With COVID-19 and Hypertension

“…ARBs/ACEIs treatment has been reported to increase the expression of ACE2, 33,34 which is also the cellular receptor for SARS-CoV-2 infection. 8 Although the downregulation of ACE2 following SARS-CoV infection has been reported to result in acute lung injury, suggesting a protective role of ACE2 upregulation and ARBs/ACEIs treatment in COVID-19, it still raised concerns that ARBs/ACEIs treatment could facilitate SARS-CoV-2 infection by increasing the expression of ACE2.…”

Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola

“…The complex relationship between the gut and other organs in critical illness has only begun to be explored (164). Experimental and human studies show that ACE2 in gut epithelial cells is necessary for normal absorption of amino acids (165,166) and glucose (167). In addition, the absence of ACE2 in gut epithelial cells alters immunity and leads to increased inflammation (165).…”

Renin-angiotensin system inhibitors in COVID-19

“…The counter-regulatory pathway involves angiotensin-converting enzyme 2 (ACE2), which cleaves angiotensin I to form angiotensin (1)(2)(3)(4)(5)(6)(7)(8)(9) and also cleaves angiotensin II to form angiotensin (1)(2)(3)(4)(5)(6)(7). This serves to decrease angiotensin II, and angiotensin (1-7) further affects vasodilation by binding to the Mas receptor.…”

“…ccjm.org Downloaded from ies. [6][7][8] Additionally, data on lung specifi c effects of RAS inhibitors on ACE2 expression or activity are lacking.…”