Overexpression of the Severe Acute Respiratory Syndrome Coronavirus-2 Receptor, Angiotensin-Converting Enzyme 2, in Diabetic Kidney Disease: Implications for Kidney Injury in Novel Coronavirus Disease 2019

Abstract

Objectives: Diabetes is associated with adverse outcomes, including death, after coronavirus disease 19 (COVID-19) infection. Beyond the lungs, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the etiologic agent of the COVID-19 pandemic, can infect a range of other tissues, including the kidney, potentially contributing to acute kidney injury in those with severe disease. We hypothesized that the renal abundance of angiotensin-converting enzyme (ACE) 2, the cell surface receptor for SARS-CoV-2, may be modulated by diabetes and agents that block the renin-angiotensin-aldosterone system (RAAS).

Methods: The expression of ACE 2 was examined in 49 archival kidney biopsies from patients with diabetic kidney disease and from 12 healthy, potential living allograft donors using next-generation sequencing technology (RNA Seq).

Results: Mean ACE 2 messenger RNA was increased approximately 2-fold in diabetes when compared with healthy control subjects (mean ± SD, 13.2±7.9 vs 7.7±3.6 reads per million reads, respectively; p=0.001). No difference in transcript abundance was noted between recipients and nonrecipients of agents that block the RAAS (12.2±6.7 vs 16.2±10.7 reads per million reads, respectively; p=0.25).

Conclusions: Increased ACE 2 messenger RNA in the diabetic kidney may increase the risk and/or severity of kidney infection with SARS-CoV-2 in the setting of COVID-19 disease. Further studies are needed to ascertain whether this diabetes-related overexpression is generalizable to other tissues, most notably the lungs.

Keywords: ACE 2; COVID-19; ECA 2; RNA Seq; RNA-Seq; SARS-CoV-2; SRAS-CoV-2; coronavirus; diabetes; diabète; kidney; reins; renin-angiotensin-aldosterone system; système rénine-angiotensine-aldostérone.

Figure 1

Violin plots showing ACE2 mRNA expression as transcript union RPMs in kidney biopsies from individuals with diabetic kidney disease (purple) and living allograft donors (red) with ACE2 expression in diabetic samples also assessed according to use (blue) or not (green) of agents that block the RAAS: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, direct renin inhibitors and mineralocorticoid receptor antagonists. ACE2, angiotensin-converting enzyme 2; mRNA, messenger RNA; RAAS, renin-angiotensin-aldosterone system; RPM, reads per million read.

Figure 2

Box plots showing ACE2 mRNA expression as transcript union RPMs in kidney biopsies from individuals with diabetic kidney disease assessed according to use of ACEis, ARBs, DRIs, diuretics and MRAs. ACE2, angiotensin-converting enzyme 2; ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; DRI, direct renin inhibitor; MRA, mineralocorticoid receptor antagonist; mRNA, messenger RNA; RPM, reads per million read.