Acatalasemia sensitizes renal tubular epithelial cells to apoptosis and exacerbates renal fibrosis after unilateral ureteral obstruction

Sunami, Reiko; Sugiyama, Hiroshi; Wang, Da Hong; Kobayashi, Mizuho; Maeshima, Yohei; Yamasaki, Yasushi; Masuoka, Noriyoshi; Ogawa, Norio; Kira, Shohei; Makino, Hírofumi

doi:10.1152/ajprenal.00266.2003

Cited by 59 publications

(56 citation statements)

References 39 publications

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“…The FOXO transcription factor functions at the G 2 /M checkpoint to induce a delay in G 2 to M progression (32). Since oxidative stress is increased in the interstitium of UUO kidneys (30), it is possible that increased levels of ␤-catenin/FOXO complex may participate in G 2 /M cell cycle arrest after UUO.…”

Section: Discussionmentioning

confidence: 99%

Klotho protects against mouse renal fibrosis by inhibiting Wnt signaling

Satoh

Nagasu

Morita

et al. 2012

American Journal of Physiology-Renal Physiology

130

102

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Augmented Wnt signaling has been implicated in many fibrotic diseases including obstructive nephropathy. Soluble form Klotho has been reported to function as a secreted Wnt antagonist. In this study, we tested whether Klotho protein could reduce renal fibrosis by inhibition of Wnt signaling. Transgenic mice that overexpressed Klotho, wild-type mice, and Klotho hetero mutant mice underwent unilateral ureteral obstruction (UUO). In some Klotho hetero mutant mice, Klotho-encoding plasmid was transferred into the skeletal muscle by electroporation. UUO induced activation of Wnt signaling in wild-type but less in Klotho transgenic mice. Enhanced tubulointerstitial fibrosis in wild-type mice was also attenuated in Klotho transgenic mice. In contrast, Wnt signaling and concomitant tubulointerstitial fibrosis were further augmented in Klotho hetero mutant mice after UUO compared with wild-type mice. In Klotho-encoding plasmid-transfected Klotho hetero mutant mice, however, Wnt signaling was markedly reduced accompanied by a decrease in extracellular matrix deposition after UUO. In vitro studies showed that stimulation of Wnt3a induced prolonged cell cycle arrest at G2/M phase, with a resultant increase in production of fibrogenic cytokines. Cotreatment with Klotho bypassed the G2/M arrest and reduced fibrogenic cytokine production. In conclusion, Klotho is a critical negative regulator of Wnt signaling and a suppressor of renal fibrosis in the obstructed kidney model.

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Section: Discussionmentioning

confidence: 99%

Klotho protects against mouse renal fibrosis by inhibiting Wnt signaling

Satoh

Nagasu

Morita

et al. 2012

American Journal of Physiology-Renal Physiology

130

102

View full text Add to dashboard Cite

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“…The role of oxidative stress has also been implicated in renal injury in the UUO model (16). Deficiency of an anti-oxidant enzyme catalase enhanced tubulointerstitial injury and fibrosis in UUO in mice (43). On the other hand, anti-oxidant agents, such fluvastatin and bioflavonoids, inhibited renal fibrosis in UUO (15,28).…”

Section: Discussionmentioning

confidence: 99%

Protective effects of low-dose carbon monoxide against renal fibrosis induced by unilateral ureteral obstruction

Wang¹,

Lee²,

Kwak³

et al. 2008

American Journal of Physiology-Renal Physiology

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Tubulointerstitial fibrosis is a hallmark of chronic progressive kidney disease leading to end-stage renal failure. An endogenous product of heme oxygenase activity, carbon monoxide (CO), has been shown to exert cytoprotection against tissue injury. Here, we explored the effects of exogenous administration of low-dose CO in an in vivo model of renal fibrosis induced by unilateral ureteral obstruction (UUO) and examined whether CO can protect against kidney injury. UUO in mice leads to increased extracellular matrix (ECM) deposition and tubulointerstitial fibrosis within 4 to 7 days. Kidneys of mice exposed to low-dose CO, however, had markedly reduced ECM deposition after UUO. Moreover, low-dose CO treatment inhibited the induction of α-smooth muscle actin (α-SMA) and major ECM proteins, type 1 collagen and fibronectin, in kidneys after UUO. In contrast, these anti-fibrotic effects of CO treatment were abrogated in mice carrying null mutation of Mkk3, suggesting involvement of the MKK3 signaling pathway in mediating the CO effects. Additionally, in vitro CO exposure markedly inhibited TGF-β1-induced expression of α-SMA, collagen, and fibronectin in renal proximal tubular epithelial cells. Our findings suggest that low-dose CO exerts protective effects, via the MKK3 pathway, to inhibit development of renal fibrosis in obstructive nephropathy.

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“…[57][58][59][60] Conversely, catalase or other antioxidants can also be administered therapeutically, in various pre-clincal models, which then prevents the onset of fibrosis. [61][62][63][64][65][66] In this context, it is interesting to note that activated myofibroblasts are known to produce and secrete hydrogen peroxide, which can have deleterious paracrine effects on adjacent normal epithelial cells.…”

confidence: 99%