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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.

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. [ABSTRACT FROM AUTHOR]

In hypertension studies, anti-inflammatory cytokine interleukin-10 (IL-10) has been shown to prevent angiotensin II (Ang II)-induced vasoconstriction and regulate vascular function by down-regulating pro-inflammatory cytokine and superoxide production in vascular cells. However, little is known about the mechanism behind the down-regulatory effect of IL-10 on Ang II-induced hypertensive mediators. In this study, we demonstrated the effects of IL-10 on expression of dimethylarginine dimethylaminohydrolase (DDAH)-1, a regulator of NO bioavailability, as well as the down-regulatory mechanism of action of IL-10 in relation to Ang II-induced hypertensive mediator expression and cell proliferation in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR). IL-10 increased DDAH-1 but not DDAH-2 expression and increased DDAH activity. Additionally, IL-10 attenuated Ang II-induced DDAH-1 inhibition in SHR VSMCs. Increased DDAH activity due to IL-10 was mediated mainly through Ang II subtype II receptor (AT 2 R) and AMP-activated protein kinase (AMPK) activation. DDAH-1 induced by IL-10 partially mediated the inhibitory action of IL-10 on Ang II-induced 12-lipoxygenase (LO) and endothelin (ET)-1 expression in SHR VSMCs. In addition, the inhibitory effect of IL-10 on proliferation of Ang II-induced VSMCs was mediated partially via DDAH-1 activity. These results suggest that DDAH-1 plays a potentially important role in the anti-hypertensive activity of IL-10 during Ang II-induced hypertension. [ABSTRACT FROM AUTHOR]

Highlights: [•] CCL5 induced DDAH activity and attenuated Ang II-induced DDAH-1 inhibition. [•] DDAH-1 induction by CCL5 was mediated by the Ang II subtype 2 receptor pathway. [•] Attenuation of hypertensive mediators by CCL5 was related to DDAH-1 activity. [•] CCL5 may be a down-regulatory factor in Ang II-induced vascular hypertension. [ABSTRACT FROM AUTHOR]

Non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastric ulcers represent a significant clinical concern and adversely affect the quality of life. Inducible nitric oxide synthase/endothelial nitric oxide synthase (iNOS/eNOS) and asymmetric dimethylarginine/ dimethylarginine dimethylaminohydrolase-1 (ADMA/DDAH-1) signaling are key players in gastric ulcer pathogenesis. This work was planned to explore the role of iNOS/eNOS and ADMA/DDAH-1 signaling in rats with indomethacin-induced gastric ulcer, as potential pathways for the gastro-protective effect of tadalafil. Split into 5 separate groups, rats were assigned to control, tadalafil (10 mg/kg, p.o), indomethacin (single oral dose of 60 mg/kg), indomethacin + pantoprazole (40 mg/kg, p.o), and indomethacin + tadalafil (10 mg/kg, p.o). The results indicated that pretreatment with tadalafil significantly reduced ulcer index (UI), increased preventive index (PI), and counteracted indomethacin-induced histopathological aberrations. Tadalafil significantly reduced the gastric content of NO while it significantly elevated that of GSH and enhanced SOD activity. It significantly reduced the gastric expression of TNF-α and ADMA while it significantly elevated that of COX-2, PGE-2, and DDAH-1. Western blot analysis revealed that pretreatment with tadalafil significantly reduced iNOS protein expression while it significantly elevated that of eNOS. Collectively, these data suggest that tadalafil exerts potential protective effect against indomethacin-induced ulcer through suppression of inflammation, attenuation of oxidative stress, and boosting of antioxidants. Moreover, tadalafil protective effects are mediated via upregulation of PGE-2 with modulating the signaling pathways of ADMA/DDAH-1, and iNOS/eNOS. As a result, the current evidence corroborates the use of tadalafil in controlling gastric ulcers and preventing NSAID gastric side effects. [Display omitted] • Tadalafil attenuated gastric histopathological damage. • It increased GSH content and SOD activity while decreased NO content. • It modulated gastric ADMA and DDAH-1 activity. • It reduced TNF-α, while increased COX-2 and PGE-2 expression. • It upregulated eNOS expression and downregulated iNOS expression. [ABSTRACT FROM AUTHOR]

The extracellular sulfatases (exSulfs) sulfatase 1 (Sulf1) and sulfatase 2 (Sulf2) are well-known regulators of cell signaling and metabolism. In addition, exSulfs mediate the up- or downregulatory effects of cytokines on angiotensin II (Ang II)-induced expression of hypertensive mediators in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHRs). Previously, we demonstrated that interleukin-10 (IL-10)-induced dimethylarginine dimethylaminohydrolase-1 (DDAH-1) expression was mediated by Ang II subtype 2 receptor (AT 2 R) and AMP-activated protein kinase (AMPK) activation, and that IL-10-mediated inhibition of Ang II-induced proliferation of SHRs VSMC was partially associated with DDAH-1. In this study, we examined the effects of exSulfs on IL-10-induced DDAH-1 expression, abrogation of Ang II-induced DDAH-1 downregulation, and inhibition of Ang II-induced proliferation of SHRs VSMC. IL-10-induced DDAH-1 expression and abrogation of Ang II-induced DDAH-1 downregulation were attenuated in Sulf1 siRNA-transfected SHRs VSMC. However, Sulf2 did not affect IL-10-induced DDAH-1 expression and abrogation of Ang II-induced DDAH-1 downregulation. Downregulation of Sulf1 inhibited IL-10-induced AT 2 R expression and the synergistic effects of IL-10 on Ang II-induced AT 2 R expression. Additionally, Sulf1 downregulation inhibited IL-10-induced AMPK activity and abrogation of Ang II-induced decrease in AMPK activity. Moreover, the IL-10-mediated inhibition of Ang II-induced proliferation was not detected in Sulf1 siRNA-transfected SHRs VSMC; IL-10-mediated inhibition of Ang II-induced VSMC proliferation was mediated via the AT 2 R pathway and AMPK activation. Specifically, IL-10-induced DDAH-1 expression, abrogation of Ang II-induced DDAH-1 downregulation, and inhibition of Ang II-induced proliferation, which is mediated by the AT 2 R pathway and AMPK activation, are mainly mediated by Sulf1 activity in SHRs VSMC. These results suggest that Sulf1, and not Sulf2, mediates the IL-10-induced inhibition of Ang II-induced hypertensive effects in SHRs VSMC. [ABSTRACT FROM AUTHOR]