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Published on: June 17, 2016
Renal asymmetric dimethylarginine inhibits fibrosis
Ming Wu1, Meijie Yuan1,2, Yanzhe Wang1,3
1Department of Nephrology, TCM Institute of Kidney Disease of Shanghai University of Traditional Chinese Medicine, Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, China.
Abstract:
Chronic kidney disease (CKD) is a worldwide public health problem that is caused by repeated injuries to the glomerulus or renal tubules. Renal fibrosis commonly accompanies CKD, and it is histologically characterized by excessive deposition of extracellular matrix proteins, such as fibronectin and collagen I, in interstitial areas. Indirect in vivo experimental data suggest that renal asymmetric dimethylarginine (ADMA) exerts antifibrotic activity in CKD. In this study, we aimed to demonstrate that renal ADMA has a direct effect on fibrosis in vivo. Normal saline, ADMA, nonsense control siRNA, Ddah1 siRNA or Ddah2 siRNA was administered into the kidney through the left ureter in a mouse model of unilateral ureteral obstruction (UUO). UUO kidneys were harvested at day 1 or 7. Western blotting was performed to assess the expression of ADMA, DDAH1 and DDAH2 and the expression of fibrotic markers, such as fibronectin, collagen I, α-smooth muscle actin, phosphorylation of Smad3 and connective tissue growth factor. Masson's trichrome staining was used to further evaluate renal fibrosis. We observed that intrarenal administration of ADMA increased the renal accumulation of ADMA and attenuated renal fibrosis at days 1 and 7. Knockdown of Ddah1 or Ddah2 increased the amount of ADMA in UUO kidneys and inhibited the expression of fibrotic proteins at days 1 and 7, which was further confirmed by Masson's staining. Thus, our in vivo data suggest that renal ADMA exerts direct antifibrotic effects in a mouse model of UUO.
Insights
Asymmetric dimethylarginine (ADMA) directly reduces kidney fibrosis in a mouse model. Increasing ADMA levels or inhibiting its breakdown enzymes protected against kidney damage and fibrotic markers in chronic kidney disease.
Area of Science:
- Nephrology
- Molecular Biology
- Pathology
Background:
- Chronic kidney disease (CKD) is a global health issue linked to renal fibrosis, characterized by excessive extracellular matrix deposition.
- Previous studies suggested renal asymmetric dimethylarginine (ADMA) has antifibrotic properties in CKD, but direct in vivo evidence was lacking.
Purpose of the Study:
- To investigate the direct in vivo antifibrotic effects of renal ADMA in a mouse model of kidney injury.
- To determine the impact of modulating ADMA levels on fibrotic markers and extracellular matrix deposition.
Main Methods:
- A mouse model of unilateral ureteral obstruction (UUO) was used to induce kidney fibrosis.
- Interventions included intrarenal administration of normal saline, ADMA, or siRNA targeting Ddah1 or Ddah2.
- Kidney tissues were analyzed using Western blotting for ADMA, DDAH1/2, and fibrotic markers, and Masson's trichrome staining for fibrosis.
Main Results:
- Intrarenal ADMA administration increased renal ADMA levels and significantly attenuated renal fibrosis.
- Knockdown of Ddah1 or Ddah2 elevated renal ADMA and inhibited the expression of key fibrotic proteins, including fibronectin and collagen I.
- These antifibrotic effects were confirmed by histological analysis of renal fibrosis.
Conclusions:
- Renal ADMA exerts direct antifibrotic effects in vivo during kidney injury.
- Modulating ADMA levels, either by direct administration or by inhibiting its degrading enzymes (DDAH1/2), represents a potential therapeutic strategy for mitigating renal fibrosis in CKD.
