The role of renin-angiotensin system in cellular differentiation: Implications in pancreatic islet cell development and islet transplantation

In addition to the well-characterized circulating renin-angiotensin system (RAS), local RAS has been identified recently in diverse tissues and organs. The presence of key components of the RAS in local tissues is important for our understanding of the patho-physiological mechanism(s) of several metabolic diseases, and may serve as a major therapeutic target for cardiometabolic syndromes. Locally generated and physiologically active RAS components have functions that are distinct from the classical vasoconstriction and fluid homeostasis actions of systemic RAS and cater specifically for local tissues. Local RAS can affect islet-cell function and structure in the adult pancreas as well as proliferation and differentiation of pancreatic stem/progenitor cells during development. Differentiation of stem/progenitor cells into insulin-expressing cells suitable for therapeutic transplantation offers a desperately needed new approach for replacement of glucose-responsive insulin producing cells in diabetic patients. Given that the generation of functional and transplantable islet cells has proven to be difficult, elucidation of RAS involvement in cellular regeneration and differentiation may propel pancreatic stem/progenitor cell development and thus β-cell regeneration forward. This review provides a critical appraisal of current research progress on the role of the RAS, including the newly characterized ACE2/Ang-(1-7)/Mas axis in the proliferation, differentiation, and maturation of pancreatic stem/progenitor cells. It is thus plausible to propose that the AT1 stimulation could be a repair mechanism involving the AT2R as well as the ACE2/Ang-(1-7)/Mas axis in directing β-cell development in diabetic patients using genetic and pharmaceutical manipulation of the RAS.