Reduced asymmetric dimethylarginine accumulation through inhibition of the type I protein arginine methyltransferases promotes renal fibrosis in obstructed kidneys

Abstract

The role of asymmetric dimethylarginine (ADMA) in chronic kidney disease (CKD) is unclear. Through inhibition of type I protein arginine methyltransferases (PRMTs), a novel strategy, we aimed to determine the effect of ADMA on renal fibrosis and explore its underlying working mechanisms. After sham or unilateral ureter ligation (UUO) operation, 20–25 g male c57 mice were treated with vehicle or PT1001B, an inhibitor of type I PRMTs, for 13 d. Moreover, human kidney 2 (HK2) and normal rat kidney 49F (NRK‐49F) cells were treated with various concentrations of PT1001B or ADMA in the presence of 2.5 ng/ml TGF‐β. We found that treatment with PT1001B increased the deposition of extracellular matrix proteins, the expression of αsmooth muscle actin, and connective tissue growth factor in UUO‐induced fibrotic kidneys, which is correlated with reduced expression of PRMT1, reduced the production of ADMA, and increased expression of uromodulin. In TGF‐β‐stimulated HK2 and NRK‐49F cells, PT1001B dose‐dependently inhibited ADMA production, increased NO concentrations, and enhanced the expression of profibrotic proteins. Exogenous addition of ADMA inhibited the expression of profibrotic proteins dose‐dependently and attenuated the profibrotic effect of PT1001B. Moreover, ADMA reduced the NO concentration in PT1001B‐treated HK2 cells. Finally, we conclude that ADMA has an antifibrotic effect in obstructed kidneys, and future application of type I PRMT inhibitor should be done cautiously for patients with CKD.—Wu, M., Lin, P., Li, L., Chen, D., Yang, X., Xu, L., Zhou, B., Wang, C., Zhang, Y., Luo, C., Ye, C. Reduced asymmetric dimethylarginine accumulation through inhibition of the type I protein arginine methyltransferases promotes renal fibrosis in obstructed kidneys. FASEB J. 33, 6948–6956 (2019). http://www.fasebj.org

Renal asymmetric dimethylarginine inhibits fibrosis

“…Moreover, kidney-specific knockdown of Ddah1 or Ddah2 gene increased the amount of renal ADMA in UUO mice, which was correlated with the reduced expression of fibrotic markers or weakened Masson's staining at days 1 and 7 in UUO kidneys. Thus, we conclude that renal ADMA is antifibrotic, which is in line with the conclusion provided by previous in vitro studies or indirect evidence using type I PRMT inhibitors or kidney-specific deletion of Ddah1 gene in mouse models of renal fibrosis [8,12]. Interestingly, a recent study showed that reduction of renal ADMA levels by intrarenal injection of adenovirus-expressing DDAH-1 ameliorates diabetic nephropathy [14].…”

“…Several in vivo and clinical studies have indicated that circulating ADMA is a risk factor and profibrotic in CKDs [10,11]. However, our previous study showed that treatment with type I PRMT inhibitor reduced renal ADMA levels and promoted renal fibrosis, suggesting that renal ADMA is antifibrotic [12]. In agreement with this conclusion, Tomlinson et al [8] showed that kidney-specific knockout of Ddah1 gene increased renal accumulation of ADMA and attenuated renal fibrosis in two different mouse models of CKD.…”

The Biological Axis of Protein Arginine Methylation and Asymmetric Dimethylarginine

“…Thus, enzymatic activities of PRMTs and DDAHs counteractively regulate the level of ADMA [51,52,53,54]. Wu et al showed that a PRMT1 inhibitor increased ADMA concentration in a dose-dependent manner both in vitro and in unilateral ureter obstructed mouse kidneys [55]. Elevated levels of ADMA are found to associate with lower DDAH2 and higher PRMT1 in cell and animal models [56,57].…”

“…In one case, concentrations of l -NMMA and ADMA were 5.2 and 5.0 µM in the endothelial cells [108]. Indeed, a recent study showed that effect of decreased ADMA correlates with enhanced NO concentration locally in renal tubules but not in the whole UUO kidney [55].…”

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

“…From our previous study, we demonstrated that circulatory levels of ADMA were increased in the diabetic kidney disease and can be used as a potential biomarker for the prediction of diabetic kidney disease at an early stage 8 . But there are limited studies on causal role of ADMA in the pathogenesis of renal diseases 18 – 20 . In our present study we are delineating the molecular mechanisms by which ADMA causes kidney cell injury under high glucose condition.…”