Restricted accessResearch articleFirst published online 2017-12
Dimethylarginine Dimethylaminohydrolase 1 Deficiency Induces the Epithelial to Mesenchymal Transition in Renal Proximal Tubular Epithelial Cells and Exacerbates Kidney Damage in Aged and Diabetic Mice
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.
Results:
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.
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