Aldosterone promotes renal interstitial fibrosis via the AIF‑1/AKT/mTOR signaling pathway

Yuan,Xueying; Wang,Xingzhi; Li,Yushu; Li,Xin; Zhang,Shuyu; Hao,Lirong

doi:10.3892/mmr.2019.10680

Aldosterone promotes renal interstitial fibrosis via the AIF‑1/AKT/mTOR signaling pathway

Authors:
- Xueying Yuan
- Xingzhi Wang
- Yushu Li
- Xin Li
- Shuyu Zhang
- Lirong Hao
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Affiliations: Department of Nephropathy and Hemodialysis, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
Published online on: September 13, 2019 https://doi.org/10.3892/mmr.2019.10680
Pages: 4033-4044
Copyright: © Yuan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

A number of studies have shown that aldosterone serves an important role in promoting renal interstitial fibrosis, although the specific mechanism remains to be elucidated. A previous study revealed that the fibrotic effect of aldosterone was associated with the expression of allograft inflammatory factor 1 (AIF‑1) in RAW264.7 macrophage cells, in a time‑ and concentration‑dependent manner. However, the exact mechanism through which aldosterone promotes renal interstitial fibrosis remains unknown. In the present study, the effects of aldosterone on renal inflammatory cell infiltration, collagen deposition and the expression levels of AIF‑1, phosphatidylinositol 3‑kinase (PI3K), AKT serine/threonine kinase (AKT), mammalian target of rapamycin (mTOR), the oxidative stress factor NADPH oxidase 2 (NOX2) and nuclear transcription factor erythroid‑related factor 2 (Nrf2) were assessed in normal rats, rats treated with aldosterone, rats treated with aldosterone and spironolactone and those treated with spironolactone only (used as the control). The effect of aldosterone on these factors was also investigated in the renal interstitium of unilateral ureteral obstruction (UUO) rats. Additionally, the AIF‑1 gene was overexpressed and knocked down in macrophage RAW264.7 cells, and the effects of aldosterone on PI3K, AKT, mTOR, NOX2 and Nrf2 were subsequently investigated. The results showed that aldosterone promoted inflammatory cell infiltration, collagen deposition and the expression of AIF‑1, PI3K, AKT, mTOR and NOX2, but inhibited the expression of Nrf2. In the UUO rats, aldosterone also promoted renal interstitial inflammatory cell infiltration, collagen deposition and the expression of AIF‑1, NOX2, PI3K, AKT and mTOR, whereas the expression of Nrf2 was downregulated by aldosterone compared with that in the UUO‑only group; the influence of aldosterone was counteracted by spironolactone in the normal and UUO rats. In vitro, aldosterone upregulated the expression levels of AKT, mTOR, NOX2 and Nrf2 in RAW264.7 cells compared with those in untreated cells. Suppressing the expression of AIF‑1 inhibited the effects of aldosterone, whereas the overexpression of AIF‑1 enhanced these effects in RAW264.7 cells. These findings indicated that aldosterone promoted renal interstitial fibrosis by upregulating the expression of AIF‑1 and that the specific mechanism may involve AKT/mTOR and oxidative stress signaling.

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