The transcription factor HNF1α induces expression of angiotensin-converting enzyme 2 (ACE2) in pancreatic islets from evolutionarily conserved promoter motifs

Pancreatic angiotensin-converting enzyme 2 (ACE2) has previously been shown to be critical for maintaining glycemia and beta-cell function. Efforts to maintain or increase ACE2 expression in pancreatic beta-cells might therefore have therapeutic potential for treating diabetes. In our study, we investigated the transcriptional role of hepatocyte nuclear factor 1 alpha (HNF1 alpha) and hepatocyte nuclear factor 1 beta (HNF1 beta) in induction of ACE2 expression in insulin-secreting cells. A deficient allele of HNF1 alpha or HNF1 beta causes maturity-onset diabetes of the young (MODY) types 3 and 5, respectively, in humans. We found that ACE2 is primarily transcribed from the proximal part of the ACE2 promoter in the pancreas. In the proximal part of the human ACE2 promoter, we further identified three functional HNF1 binding sites, as they have binding affinity for HNF1 alpha and HNF1 beta and are required for induction of promoter activity by HNF1 beta in insulinoma cells. These three sites are well-conserved among mammalian species. Both HNF1 alpha and HNF1 beta induce expression of ACE2 mRNA and lead to elevated levels of ACE2 protein and ACE2 enzymatic activity in insulinoma cells. Furthermore, HNF1 alpha dose-dependently increases ACE2 expression in primary pancreatic islet cells. We conclude that HNF1 alpha can induce the expression of ACE2 in pancreatic islet cells via evolutionarily conserved HNF1 binding sites in the ACE2 promoter. Potential therapeutics aimed at counteracting functional HNF1 alpha depletion in diabetes and MODY3 will thus have ACE2 induction in pancreatic islets as a likely beneficial effect. (C) 2013 Elsevier B.V. All rights reserved.