THE ARGINASE-NO AXIS IN TYPE 2 DIABETES AND DIABETIC NEPHROPATHY: A CROSS-SECTIONAL STUDY

Abstract

The aim of this study was to characterize the arginase-NO axis in type 2 diabetes mellitus (T2DM) with and without nephropathy versus control subjects. We performed a cross-sectional comparative study including 181 individuals, divided into three groups: 60 patients with Diabetic nephropathy (DN), 60 T2DM patients without nephropathy (DM2), and 61 healthy controls. The serum activity of arginase was measured by a colorimetric assay and the levels of nitrites and nitrates by the Griess reaction method. The estimated glomerular filtration rate (eGFR) was calculated by the CKD-EPI 2021 equation. In diabetic patients, the level of arginase was higher than in the control group (DN: 9.69 ± 2.16 U/L; DM2: 11.06 ± 2.35 U/L; Control: 7.84 ± 1.07 U/L; p < 0.001). Both nitrite and nitrate levels were lower in diabetic patients (p < 0.001). The L-arginine metabolic pathway plays an important role in vascular dysfunction in diabetes via competing actions of two enzymes: nitric oxide synthase (NOS) and arginase. DN is one of the main causes of end-stage renal disease around the world. Strong negative correlations of arginase with nitrate (r = -0.517, p < 0.001) and nitrite (r = -0.519, p < 0.001) were found in the DN group. All groups exhibited strong positive correlations between nitrite and nitrate (r = 0.884 in DN, p < 0.001). Serum creatinine levels had a strong negative correlation with arginase activity in the DN group (r = -0.844, p < 0.001). Conclusions: Elevated arginase is not unique to DN but a feature of diabetes. Inverse correlations of arginase with NO metabolites further validate the hypothesis of arginase being involved in decreasing NO availability. Strong correlation of nitrite with nitrate indicates an internal connectivity of the NO pathway, although it is perturbed by diabetes. Arginase is a potential therapeutic target and NO metabolites are potential biomarkers of endothelial dysfunction in diabetes.