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Hepatocyte nuclear factor 1α stimulates the compensatory axis of the renin‐angiotensin system in the pancreatic islet by specific induction of angiotensin‐converting enzyme 2 (ACE2)

Our laboratory has previously demonstrated that elevated pancreatic expression of angiotensin‐converting enzyme 2 (ACE2) protects beta‐cell function in diabetic mice. We have also shown that hepatocyte nuclear factor 1α (HNF1α) induces ACE2 expression in insulinoma cells. We hypothesized that HNF1α induces the compensatory axis (ACE2, Angiotensin‐(1–7), Mas) of the renin‐angiotensin system (RAS) that counteracts angiotensin II effects in the pancreatic islet. Primary cells from pancreatic islets isolated from wild‐type mice were infected with an adenovirus for expression of HNF1α or a control adenovirus. Components of the RAS which mediate signaling by angiotensin II (angiotensinogen, renin, prorenin receptor, angiotensin‐converting enzyme, angiotensin receptor type 1a, angiotensin receptor type 2) as well as components of the compensatory RAS axis were quantified by quantitative RT‐PCR. The only mRNA of the RAS that was substantially (4‐fold) induced in islet cells was ACE2 mRNA. While angiotensinogen and angiotensin receptor type 2 transcripts were significantly induced by HNF1α in a mouse insulinoma cell line, the induction was much smaller (4‐ and 9‐fold) than for ACE2 mRNA (>;100‐fold). We conclude that ACE2 is the most sensitive RAS target of HNF1α. Through induction of ACE2, HNF1α may thus counteract deleterious effects of angiotensin II on beta‐cell function. Support: NIH/NIDDK (DK084466).