DDAH1
N(G),N(G)-dimethylarginine dimethylaminohydrolase 1 (EC 3.5.3.18) (DDAH-1) (Dimethylarginine dimethylaminohydrolase 1) (DDAHI) (Dimethylargininase-1) [DDAH]
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Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is mainly degraded by dimethylarginine dimethylaminohydrolase (DDAH). Emerging evidence suggests that plasma ADMA accumulation and DDAH1 activity/expression reduction are linked to chronic kidney disease (CKD) pathology, but the mechanisms remain largely unknown. Here, we examined the role of ADMA/DDAH1 in the epithelial-mesenchymal transition (EMT) of tubular epithelial cells (TECs), an important mechanism for the pathogenesis of renal fibrosis. In HK-2 cells, DDAH1 expression was reduced by aldosterone treatment, and overexpression of DDAH1 significantly attenuated aldosterone-induced EMT. More interestingly, DDAH1 deficiency resulted in EMT-related changes in primary TECs via increasing oxidative stress, impairing adenosine monophosphate-activated kinase (AMPK) signaling, and downregulating of peroxiredoxin 5 (Prdx5). However, those effects could not be mimicked by increasing the ADMA concentration. After regular feeding for 24 months or inducing type 2 diabetes, Ddah1 mice had higher serum creatinine levels than wild-type (WT) mice. In the kidneys of the aged or diabetic mice, loss of DDAH1 resulted in more interstitial fibrosis, more collagen deposition, and greater induction of EMT-related changes and oxidative stress than in the WT kidneys. Innovation and Conclusion: Our results provide the first direct evidence that the DDAH1 has a marked effect on kidney fibrosis and oxidative stress induced by aging or diabetes. Our findings suggest that strategies to increase DDAH1 activity in TECs may provide a novel approach to attenuate CKD development. Antioxid. Redox Signal. 27, 1347-1360.
MeSH Terms
- Aging
- Aldosterone
- Amidohydrolases
- Animals
- Arginine
- Cell Line
- Creatinine
- Diabetes Mellitus, Experimental
- Disease Models, Animal
- Epithelial Cells
- Epithelial-Mesenchymal Transition
- Fibrosis
- Gene Knockout Techniques
- Humans
- Kidney Diseases
- Kidney Tubules, Proximal
- Mice
Keywords
- ADMA
- AMPK
- DDAH1
- EMT
- ROS
Aging-related ED is predominantly attributed to neurovascular dysfunction mediated by NO suppression and increased oxidative stress in penis. The alterations of protein arginine methyltransferases 1 (PRMT1)/dimethylarginine dimethylaminohydrolase (DDAH)/asymmetrical dimethylarginine (ADMA)/NO synthase (NOS) pathway regulate NO production in the vascular endothelium. Epigallocatechin-3-gallate (EGCG) is one of the most abundant and antioxidative ingredients isolated from green tea. In the present study, 40 Sprague-Dawley rats were randomly distributed into four groups: one young rat group and three aged rat groups treated with daily gavage feedings of EGCG at doses of 0, 10 mg kg-1 and 100 mg kg-1 for 12 weeks, respectively. Erectile function was assessed by electrical stimulation of the cavernous nerves with intracavernous pressure (ICP) measurement. After euthanasia, penile tissue was investigated using Western blot and ELISA to assess the PRMT1/DDAH/ADMA/NOS metabolism pathway. Superoxide dismutase (SOD) and malondialdehyde (MDA) levels were detected by colorimetry. We also evaluated smooth muscle contents. The ratio of maximal ICP and mean systemic arterial pressure (MAP) was markedly higher in EGCG-treated aged rats than in untreated aged rats. We found that DDAH1 and DDAH2 were expressed in cavernosal tissue, and they were downregulated in corpora of aged rats. The administration of EGCG upregulated the expression and activity of DDAH. In contrast, EGCG treatment downregulated the expression of PRMT1 and ADMA content. Moreover, EGCG-treated rats showed an improvement in smooth muscle expression, the ratio of smooth muscle cell/collagen fibril, SOD activity, and MDA levels when compared with untreated aged rats.
MeSH Terms
- Aging
- Amidohydrolases
- Animals
- Antioxidants
- Arginine
- Arterial Pressure
- Catechin
- Cyclic GMP
- Erectile Dysfunction
- Male
- Muscle, Smooth
- Nitric Oxide Synthase
- Penile Erection
- Penis
- Protein-Arginine N-Methyltransferases
- Rats
- Rats, Sprague-Dawley
- Signal Transduction
- Superoxide Dismutase-1