Putative roles of kinin receptors in the therapeutic effects of angiotensin 1-converting enzyme inhibitors in diabetes mellitus

The role of endogenous kinins and their receptors in diabetes mellitus is being confirmed with the recent developments of molecular and genetic animal models. Compelling evidence suggests that the kinin B-2 receptor is organ-protective and partakes to the therapeutic effects of angiotensin 1-converting enzyme inhibitors (ACEI) and angiotensin AT(1), receptor antagonists. Benefits derive primarily from vasodilatory, antihypertensive, antiproliferative, antihypertrophic, antifibrotic, antithrombotic and antioxidant properties of kinin B-2 receptor activation. Mechanisms include the formation of nitric oxide and prostacyclin and the inhibition of NAD(P)H oxidase activity involving classical and novel signalling pathways. Kinin B-2 receptor also ameliorates insulin resistance by increasing glucose uptake and supply, and by inducing glucose transporter-4 translocation either directly or through phosphorylation of insulin receptor. The kinin B-1 receptor, which is induced by the cytokine network, growth factors and hyperglycaemia, mediates hyperalgesia, vascular hyperpermeability and leukocytes infiltration in diabetic animals. However, emerging data highlight reno- and cardio-protective effects mediated by kinin B-1 receptor under chronic ACEI therapy in diabetes mellitus. Thus, the Janus-faced of kinin receptors needs to be taken into account in future drug development. For instance, locally acting kinin B-1/B-2 receptor agonists if used in a safe therapeutic window may represent a more rationale strategy in the prevention and management of diabetic complications. Because kinin B-2 receptor antagonists may further increase insulin resistance, the persisting dogma that restricts the development of kinin receptor analogues to antagonists (that is still relevant to abrogate pain and inflammation) needs to be revisited. (C) 2004 Elsevier B.V. All rights reserved.