Low-Dose Radiation Activates Akt and Nrf2 in the Kidney of Diabetic Mice: A Potential Mechanism to Prevent Diabetic Nephropathy

Abstract

Repetitive exposure of diabetic mice to low-dose radiation (LDR) at 25 mGy could significantly attenuate diabetes-induced renal inflammation, oxidative damage, remodeling, and dysfunction, for which, however, the underlying mechanism remained unknown. The present study explored the effects of LDR on the expression and function of Akt and Nrf2 in the kidney of diabetic mice. C57BL/6J mice were used to induce type 1 diabetes with multiple low-dose streptozotocin. Diabetic and age-matched control mice were irradiated with whole body X-rays at either single 25 mGy and 75 mGy or accumulated 75 mGy (25 mGy daily for 3 days) and then sacrificed at 1–12 h for examining renal Akt phosphorylation and Nrf2 expression and function. We found that 75 mGy of X-rays can stimulate Akt signaling pathway and upregulate Nrf2 expression and function in diabetic kidneys; single exposure of 25 mGy did not, but three exposures to 25 mGy of X-rays could offer a similar effect as single exposure to 75 mGy on the stimulation of Akt phosphorylation and the upregulation of Nrf2 expression and transcription function. These results suggest that single 75 mGy or multiple 25 mGy of X-rays can stimulate Akt phosphorylation and upregulate Nrf2 expression and function, which may explain the prevention of LDR against the diabetic nephropathy mentioned above.

Additive protection by LDR and FGF21 treatment against diabetic nephropathy in type 2 diabetes model

“…Expression of the above-mentioned antioxidants is regulated positively by the transcription factor Nrf2. We demonstrated previously that Nrf2 is upregulated in diabetic mice exposed to LDR (51,57). Therefore, we next determined whether the altered antioxidant expression in the DM/LDR and DM/Com groups was due to altered renal Nrf2 levels (Fig.…”

“…The available data suggest that preexposure to LDR reduces the incidence of alloxaninduced diabetes and also delays the onset of hyperglycemia in diabetes-prone nonobese diabetic mice (46,48). This protection is associated with the prevention of oxidative damage (51)(52)(53)57). Our previous study revealed that, in addition to antioxidative effects, LDR also prevents inflammation to protect against DN (43,51,55,56).…”

“…This protection is associated with the prevention of oxidative damage (51)(52)(53)57). Our previous study revealed that, in addition to antioxidative effects, LDR also prevents inflammation to protect against DN (43,51,55,56). Patients with DN have poor renal function; however, most drugs used to treat DN are excreted through the kidney, which further increases the renal working load in diabetic patients.…”

“…In addition, our previous studies (43) showed that exposure to LDR greatly prevented type 2 diabetes-induced renal injury and also inhibited renal oxidative stress, inflammation, and fibrosis without altering blood glucose levels. We (51,57) further demonstrated that LDR could increase Akt phosphorylation and the expression of Nrf2 and its downstream antioxidants significantly.…”

“…FGF21 might mainly suppress the systemic pathogenesis, whereas LDR might protect the kidneys from diabetes mainly via anti-inflammatory, antioxidative, and antifibrotic mechanisms (51,56,57). Therefore, the aim of the present study was to investigate whether the combination treatment with LDR and FGF21 could exert additive effects on the prevention of DN via both systemic and renal mechanisms.…”