Improving the Innate Immune Response in Diabetes by Modifying the Renin Angiotensin System

Abstract

Patients with Type 2 Diabetes Mellitus (T2DM) suffer from a higher incidence and severity of pulmonary infections. This is likely due to immune impairment and structural abnormalities caused by T2DM-induced oxidative stress (OS) and chronic inflammation. Modulation of the Renin Angiotensin System (RAS) through blockade of the actions of angiotensin II (AII), or inducing the protective pathway, has the potential to reduce these pathological pathways. The effects of Angiotensin 1-7 [A(1-7)] and NorLeu 3-A(1-7) [NorLeu], ligands of the protective RAS, on the innate immune response were evaluated in the db/db mouse model of T2DM. Only NorLeu treatment reduced the structural pathologies in the lung caused by T2DM. A decreased in bactericidal activity and phagocytosis in diabetic animals was also observed; both A(1-7) and NorLeu treatment restored these functions. Myeloid progenitor CFUs were reduced and neutrophil/progenitor OS was increased in saline-treated db/db mice, and was reversed by A(1-7) and NorLeu treatment. These results demonstrate the adverse effects of diabetes on factors that contribute to pulmonary infections and the therapeutic potential of protective RAS peptides. Overall, RAS-modification may be a viable therapeutic target to treat diabetic complications that are not addressed by glucose lowering drugs.

Angiotensin-(1-7)/MasR axis promotes migration of monocytes/macrophages with a regulatory phenotype to perform phagocytosis and efferocytosis

“…Given that Ang-(1-7)/MasR increased the phagocytic activity of macrophages to bacteria, we hypothesize that this mixed phenotype of macrophages induced by Ang-(1-7) preserves the macrophage antimicrobial responses while preventing exacerbations of inflammation. Indeed, previous studies have observed that harnessing this alternative branch of the RAS using agonists of MasR favors the phagocytic activity of dysfunctional neutrophils of diabetic animals ( 70 ). Our self-resolving model of E .…”

Targeting the Protective Arm of the Renin-Angiotensin System to Reduce Systemic Lupus Erythematosus Related Pathologies in MRL-lpr Mice

“…Our lab and others have demonstrate the cardio-protective and reno-protective effects of A(1-7) in a number of animal models ( 32 , 39 – 46 ). Of note, several published and unpublished studies in our lab have shown different outcomes with A(1-7) vs. NorLeu treated mice in various disease models ( 47 ). The different results seen here with A(1-7) vs. NorLeu treated mice and those seen in past studies are likely due to differential binding patterns to all the known A(1-7) targets which include; AT1R ( 48 , 49 ), AT2R ( 50 – 53 ), ACE ( 54 – 56 ), Mas ( 57 ), and MrgD ( 58 ).…”

Countermeasure and therapeutic: A(1–7) to treat acute respiratory distress syndrome due to COVID-19 infection

“…19,20 Long and short-term administration of A(1-7) treatment in diabetic mice has improved lung, heart and kidney function by reducing oxidative stress and inflammation. [21][22][23][24] In diabetic mice, Resident alveolar macrophages are depleted in diabetic mice and restored to normal levels with A(1-7) treatment. 24 Further, data from SARS patients suggests that disease severity is correlated with an immune dysregulation in neutrophil clearance commonly seen in diabetic patients.…”

“…[21][22][23][24] In diabetic mice, Resident alveolar macrophages are depleted in diabetic mice and restored to normal levels with A(1-7) treatment. 24 Further, data from SARS patients suggests that disease severity is correlated with an immune dysregulation in neutrophil clearance commonly seen in diabetic patients. Again, A(1-7) has been shown to restore proper pathogen clearance and immune resolution of neutrophils.…”