Methionine sulfoxide reductase A deficiency exacerbates progression of kidney fibrosis induced by unilateral ureteral obstruction.

Methionine sulfoxide reductase A (MsrA), which stereospecifically catalyzes the reduction of methionine-S-sulfoxide, is an important reactive oxygen species (ROS) scavenger. Tissue fibrosis is a maladaptive repair process following injury, associated with oxidative stress. In this study, we investigated the role of MsrA in unilateral ureteral obstruction (UUO)-induced kidney fibrosis and its underlying mechanisms by using MsrA gene-deleted mice (MsrA(-/-)). MsrA deletion increased collagen deposition in the interstitium and the expression of collagen III and α-smooth muscle actin in the UUO kidneys, indicating that MsrA deficiency exacerbated the progression of UUO-induced kidney fibrosis. UUO reduced the kidney expression of MsrA, MsrB1, and MsrB2, thereby decreasing MsrA and MsrB activity. UUO increased hydrogen peroxide and lipid peroxidation levels and the ratio of oxidized glutathione (GSSG) to total glutathione (GSH) in the kidneys. The UUO-induced elevations in the levels of these oxidative stress markers and leukocyte markers were much higher in the MsrA(-/-) than in the MsrA(+/+) kidneys, the latter suggesting that the exacerbated kidney fibrosis in MsrA(-/-) mice was associated with enhanced inflammatory responses. Collectively, our data suggest that MsrA plays a protective role in the progression of UUO-induced kidney fibrosis via suppression of fibrotic responses caused by oxidative stress and inflammation.

Kim JI ，Noh MR ，Kim KY ，Jang HS ，Kim HY ，Park KM ... -  《-》

Orchiectomy attenuates kidney fibrosis after ureteral obstruction by reduction of oxidative stress in mice.

Men are generally more prone to chronic kidney disease and progression to end-stage renal disease than women. However, the underlying mechanisms remain unclear. In this study, we investigated the role of reactive oxygen species and testosterone in the progression of renal fibrosis in mice with unilateral ureteral obstruction (UUO). Mice were subjected to either orchiectomy or sham operation 14 days before either UUO or sham surgery. Harvesting of the kidney was performed 7 days after the UUO surgery to measure the production of reactive oxygen species and expression of antioxidants such as catalase, copper-zinc superoxide dismutase, and manganese superoxide dismutase, as well as fibrosis markers including α-smooth muscle actin (α-SMA) and collagen. UUO resulted in increased expression of α-SMA and collagen deposition in the kidneys of both female and male mice. These increases were significantly greater in males than females. Orchiectomy significantly reduced increases in α-SMA expression and collagen deposition when compared with intact male. UUO increased the production of hydrogen peroxide and lipid peroxidation along with the decreases in expression of manganese superoxide dismutase, copper-zinc superoxide dismutase, and catalase. These changes induced by UUO were significantly attenuated by orchiectomy. Males are more susceptible to UUO-induced kidney fibrosis compared with females, and the higher susceptibility of males is obviated by orchiectomy along with reduction in oxidative stress.

Cho MH ，Jung KJ ，Jang HS ，Kim JI ，Park KM ... -  《-》

Involvement of hydrogen sulfide and homocysteine transsulfuration pathway in the progression of kidney fibrosis after ureteral obstruction.

Hydrogen sulfide (H2S) produced by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) in the transsulfuration pathway of homocysteine plays a number of pathophysiological roles. Hyperhomocysteinemia is involved in kidney fibrosis. However, the role of H2S in kidney fibrosis remains to be defined. Here, we investigated the role of H2S and its acting mechanism in unilateral ureteral obstruction (UO)-induced kidney fibrosis in mice. UO decreased expressions of CBS and CSE in the kidney with decrease of H2S concentration. Treatment with sodium hydrogen sulfide (NaHS, a H2S producer) during UO reduced UO-induced oxidative stress with preservations of catalase, copper-zinc superoxide dismutase (CuZnSOD), and manganese superoxide dismutase (MnSOD) expression, and glutathione level. In addition, NaHS mitigated decreases of CBS and CSE expressions, and H2S concentration in the kidney. NaHS treatment attenuated UO-induced increases in levels of TGF-β1, activated Smad3, and activated NF-κB. This study provided the first evidence of involvement of the transsulfuration pathway and H2S in UO-induced kidney fibrosis, suggesting that H2S and its transsulfuration pathway may be a potential target for development of therapeutics for fibrosis-related diseases.

Jung KJ ，Jang HS ，Kim JI ，Han SJ ，Park JW ，Park KM ... -  《-》

Exogenous hydrogen sulfide prevents kidney damage following unilateral ureteral obstruction.

To investigate the protective effects of exogenous hydrogen sulfide (H2 S) against unilateral ureteric obstruction (UUO) induced renal injury and explore the potential mechanisms involved. Rats were randomly divided into four groups: sham group, UUO group, UUO + saline group, and UUO + NaHS group. Rats were sacrificed on Day 10 after UUO. The tubulointerstitial injury, interstitial fibrosis, and the infiltrating of macrophages in the interstitium were assessed. Expression of TNF-α in kidney tissue was also measured. Oxidative stress was evaluated by detecting the level of MDA and SOD in renal tissues. Interstitial fibrosis and renal injury score were markedly increased on Day 10 after UUO. In contrast, administration of NaHS significantly reduced the injury score. In addition, the kidneys that were treated with NaHS exhibited minimal interstitial fibrosis. The number of ED1 positive cells in the interstitium and the level of TNF-α were significantly higher in UUO kidneys compared with that in sham group. NaHS treatment significantly attenuated infiltration of macrophages and the expression of TNF-α. Our findings showed a significant increase in MDA level and decrease in the SOD activity in the UUO group compared to the sham group. However, significant decrease in MDA level and increase in SOD activity were observed after treatment of NaHS. Our study demonstrates that NaHS protects against UUO-induced renal damage via attenuating fibrosis, oxidative stress, and inflammation. Therefore, H2 S may be useful as a potential candidate in the treatment of renal damage induced by obstruction. Neurourol. Urodynam. 33:538-543, 2014. © 2013 Wiley Periodicals, Inc.

Jiang D ，Zhang Y ，Yang M ，Wang S ，Jiang Z ，Li Z ... -  《-》

KS370G, a caffeamide derivative, attenuates unilateral ureteral obstruction-induced renal fibrosis by the reduction of inflammation and oxidative stress in mice.

Unilateral ureteral obstruction (UUO) is an established animal model used to study renal nephropathy. Caffeic acid phenethyl ester, a natural phenolic compound, possesses antifibrotic, anti-inflammation and anti-oxidative stress effects; however, rapid decomposition by esterases substantially decreases its bioavailability. The goal of this study was to investigate the beneficial effects of KS370G, a synthetic caffeamide derivative, on UUO-induced renal injury. Following the UUO, KS370G (10mg/kg) was administered by oral gavage once a day. Renal injury was analyzed at 14 days post-operation. Our results show that KS370G significantly attenuated collagen deposition in the obstructed kidney and inhibited UUO-induced renal fibrosis markers expression, including fibronectin, type I collagen, vimentin, and α-smooth muscle actin (α-SMA). KS370G significantly lowered the expression of renal inflammatory chemokines/adhesion molecules and monocyte cells marker (MCP-1, VCAM-1, ICAM-1 and CD11b). KS370G also reduced renal malondialdehyde levels and reversed the expression of renal antioxidant enzymes (SOD and catalase) after UUO. Furthermore, KS370G significantly inhibited UUO-induced elevated plasma AngII and TGF-β1 levels, TGF-β1 protein expression and Smad3 phosphorylation. These findings demonstrate that KS370G reduces renal obstructive nephropathy by possibly inhibiting AngII, TGF-β and Smad3 signaling pathways.

Chuang ST ，Kuo YH ，Su MJ 《-》