D‑Pinitol alleviates cyclosporine A‑induced renal tubulointerstitial fibrosis via activating Sirt1 and Nrf2 antioxidant pathways

Koh,Eun   Sil; Kim,Soojeong; Kim,Minyoung; Hong,Yu   Ah; Shin,Seok   Joon; Park,Cheol  Whee; Chang,Yoon   Sik; Chung,Sungjin; Kim,Ho‑Shik

doi:10.3892/ijmm.2018.3408

D‑Pinitol alleviates cyclosporine A‑induced renal tubulointerstitial fibrosis via activating Sirt1 and Nrf2 antioxidant pathways

Authors:
- Eun Sil Koh
- Soojeong Kim
- Minyoung Kim
- Yu Ah Hong
- Seok Joon Shin
- Cheol Whee Park
- Yoon Sik Chang
- Sungjin Chung
- Ho‑Shik Kim
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Affiliations: Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea, Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
Published online on: January 19, 2018 https://doi.org/10.3892/ijmm.2018.3408
Pages: 1826-1834
Copyright: © Koh et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Although the mechanism of cyclosporine A (CsA)‑induced renal injury remains to be fully elucidated, accumulating evidence suggests that oxidative stress is critical in producing CsA‑induced structural and functional renal impairment. The present study investigated the effect of D‑pinitol, a cyclitol present in soybean, on chronic CsA nephropathy. Male ICR mice were treated with vehicle, CsA (30 mg/kg/day), D‑pinitol (50 mg/kg/day) or a combination of CsA and D‑pinitol for 28 days. To assess which pathway responding to oxidative stress is augmented by D‑pinitol, the expression levels of several antioxidant enzymes and their possible regulators were measured. Treatment with D‑pinitol significantly suppressed the increase of serum creatinine and decrease of urine osmolality, compared with the CsA control group. Histological examination of Masson's trichrome‑ and α‑smooth muscle actin‑stained renal tissue demonstrated that the CsA‑induced tubulointerstitial fibrosis and inflammation were attenuated by D‑pinitol. Following the administration of D‑pinitol, there were increased expression levels of heme oxygenase‑1, NAD(P)H:quinone oxidoreductase 1, superoxide dismutase 1 and catalase in CsA‑treated kidneys. In addition, D‑pinitol increased the level of sirtuin 1 (Sirt1), and the total and nuclear expression levels of nuclear erythroid factor 2‑related factor 2 (Nrf2), suggesting that activation of the Sirt1 and Nrf2 pathways may induce the cellular antioxidant system against CsA‑induced nephropathy. Collectively, these data suggested that D‑pinitol may protect the kidney from CsA‑induced fibrosis, and that this renoprotective effect of D‑pinitol was due to the inhibition of oxidative stress through the activation of Sirt1 and Nrf2, and the subsequent enhancement of antioxidant enzymes.

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