Dysregulation of dimethylargininedimethylaminohydrolase/asymmetric dimethylarginine pathway in rat type II diabetic nephropathy

Abstract

An impaired generation of nitric oxide has been associated with diabetic renal disease. In order to elucidate the underlying molecular mechanisms into how nitric oxide synthesis is impaired in diabetic renal disease, we examined changes in activities and expressions of some renal enzymes involved in nitric oxide production during the development of diabetic nephropathy in type II diabetic Otsuka Long-Evans Tokushima Fatty rats. Ten-week old Otsuka Long-Evans Tokushima Fatty (n = 40) and control Long-Evans Tokushima Otsuka rats (n = 20) were given drinking water containing 20% sucrose to accelerate the development of diabetic nephropathy. Otsuka Long-Evans Tokushima Fatty rats developed diabetic nephropathy in an age-dependent manner. Renal nitric oxide synthase activities in Otsuka Long-Evans Tokushima Fatty rats gradually declined with the progression of diabetic mellitus and were significantly lower than those of age-matched Long-Evans Tokushima Otsuka rats after 22 weeks of age. The lower activities of renal nitric oxide synthase in Otsuka Long-Evans Tokushima Fatty rats were correlated with relatively higher levels of renal free asymmetric dimethylarginine, an endogenous nitric oxide synthase inhibitor, and were also correlated with decreased activities of dimethylargininedimethylaminohydrolase which metabolizes asymmetric dimethylarginine to citrulline. These results imply that dimethylargininedimethylaminohydrolase dysregulation may play an important role in the development of diabetic nephropathy by increasing asymmetric dimethylarginine levels, which leads to inhibition of renal nitric oxide synthesis.

DDAH2 alleviates myocardial fibrosis in diabetic cardiomyopathy through activation of the DDAH/ADMA/NOS/NO pathway in rats

“…Treatment against fibrosis with the early utilization of angiotensin-converting enzyme inhibitors may be a potential diabetic strategy (11). Dimethylarginine dimethylaminohydrolase (DDAH) dysregulation has been found to exert notable effect during the progression of diabetic nephropathy through elevating asymmetric dimethylarginine levels (12). Therefore, the present study investigated the role of DDAH2 under experimental diabetic conditions to test the hypothesis that DDAH2 dysregulation is involved in the progression of fibrosis in DCM.…”

Association of amino acids related to urea cycle with risk of diabetic nephropathy in two independent cross-sectional studies of Chinese adults

“…NO is identified as an important regulator of renal function and morphology ( 28 ). Asymmetric dimethylarginine can be metabolized to citrulline, which potentially prevents the inhibition of endothelial nitric oxide synthase by asymmetric dimethylarginine ( 29 ). The elevation level of citrulline in DN patients may be related to dysregulation of the renal NO-producing system.…”

Asymmetric dimethylarginine (ADMA) accelerates renal cell fibrosis under high glucose condition through NOX4/ROS/ERK signaling pathway

“…By impairing the production of nitric oxide, ADMA contributes to the development of vascular malfunctioning 16,17 . Many studies have reported that elevated ADMA concentration in the circulation is a potential biomarker for the prediction of cardiovascular diseases.…”