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 ... -  《-》

Wen-pi-tang-Hab-Wu-ling-san reduces ureteral obstructive renal fibrosis by the reduction of oxidative stress, inflammation, and TGF-beta/Smad2/3 signaling.

Kidney fibrosis results in chronic renal disease. The current treatment of chronic renal diseases is limited to angiotensin converting enzyme inhibitors and angiotensin receptor blockers. Recently, we found that Wen-pi-tang-Hab-Wu-ling-san (WHW) extract, which has been used to treat renal diseases in herbal medicine for a long time, plays anti-fibrogenic. Here, we investigated the role of WHW in the kidney fibrosis induced by unilateral ureteral obstruction (UUO) in mice. C57BL/6 male mice were subjected to UUO on day 0 and then administered with either WHW (2, 10, or 50 mg/kg of body weight) or vehicle orally from 1 day after UUO to finish the experiment. WHW-administration significantly mitigated the UUO-induced kidney fibrotic changes including tubular atrophy and dilatation, collagen accumulation, expansion of interstitial space and leukocyte infiltration. WHW prevented the increases of oxidative stress by the prevention of UUO-induced decreases of catalase, copper-zinc superoxide dismutase (CuZnSOD) and manganese superoxide dismutase (MnSOD), resulting in reduced production of oxidative stress. Furthermore, WHW reduced transforming growth factor-beta (TGF-beta) expression and phosphorylation of Smad2/3 stimulated by UUO. In conclusion, WHW prevented kidney fibrosis following UUO by the inhibition of inflammation, oxidative stress and TGF-beta/Smad2/3 signaling pathway.

Jung KJ ，Kim J ，Park YK ，Yoon YR ，Park KM ... -  《-》

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 ... -  《-》

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 《-》

[Effects of reduced glutathione on contents of hydroxyproline and oxidation stress reaction in kidney of unilateral ureteral obstruction in rat].

Na Y ，Zhang XX ，Zhang XD ，Yuan HP ，Hu XL ，Zheng W ，Li G ... -  《-》