The Mechanism And Optimal Conditions Of Low-dose Radiation In Prevention And Treatment Of Diabetic Kidney Disease

Background and objective:Today there are387million people living with diabetes, and a vast amount of people with diabetes are progressing towards complications. Diabetic kidney disease (DKD) is one of the most severe complications and is the major cause of end stage renal disease (ESRD). Early diagnosis and treatment can reduce the development and progression of DKD, and reduce the morbidity and mortality associated with DKD. However, no effectively preventive or therapeutic approaches are available currently. The efficacy of common treatments remains a concern. For no single approach is able to efficiently prevent DKD and medications all have potential toxic side-effects for different organs. Most of the patients with DKD finally need regular dialysis treatment and even renal transplantation. Hence, new and preferable methods which can prevent and delay the progression of DKD at the early stage and have little toxic side-effects are urgently needed.It has been well known that low-dose radiation (LDR) often elicits hormesis and adaptive response. It was documented for the stimulation of antioxidative function, immune, anti-inflammatory functions. In addition, lots of experimental studies have shown that it could reduce the frequency of mutations, decrease the rate of chromosome inversions, and reduce the rate of neoplastic transformation to below spontaneous level. Our preliminary study showed that LDR at25mGy significantly suppressed diabetes-induced renal dysfunction, but had mild toxic effects and there was no significant difference for the renal improvement between the8-week and12-week LDR exposures. So whether the condition is optimal and safe for diabetic patients and the mechanism of LDR to protect the kidney from diabetes remain unclear. In this study, we strived to optimize LDR conditions including dose, frequency and mode in order to get the greatest and safest effect on DKD, and explore the mechanism of the protective effect of LDR on DKD. This may bring forth a new idea for clinical patients with DKD.Methods:Type1diabetes were induced in male C57BL/6J mice by multiple injections of low-dose streptozotocin. Diabetic or age-matched normal mice received X-irradiation at a dose of12.5,25or50mGy every other day, or exposure of different frequency (every other day or weekly), or exposure of different modes (whole body or renal region) for either4or8weeks. Blood glucose, renal function, oxidative and fibrotic factors, and histopathological changes were examined at the4th and8th week of the study.Results:The renal dysfunction in diabetic mice was shown by the decreased creatinine and increased microalbumin in the urine. Renal oxidative damage, detected by protein nitration and lipid oxidation, and remodeling, reflected by increased expression of CTGF (connective tissue growth factor), Col IV(collagen IV) and FN (fibronectin), were significantly increased in diabetic mice. All these renal pathological and function changes in diabetic mice were markedly attenuated by exposure to LDR at all regimens at the4th and8th week of the study. LDR did not affect blood glucose either in normal or in diabetic mice at the4th week. However, blood glucose levels, examined at the8th week of this study, were significantly decreased in the mice of all DM/L groups. It also showed obvious attenuation of symptoms of polydipsia, polyphagia, polyuria and weight loss, improvement of the general state and fur color and hair gloss in diabetic mice with LDR. Furthermore, LDR at12.5mGy every other day in whole body for8weeks improved microalbumin in the urine,4-HNE,3-NT, FN, Col IV, CTGF and renal histopathological changes better than other two doses (25mGy and50mGy), but it still had very mild toxic side-effects. After prolongation of the exposure interval, we found LDR at25mGy once a week had a similar beneficial effect and had no significant side-effect. Moreover, renal region exposure provided a better protection against diabetes-induced renal oxidative damage and fibrosis compared with whole body exposure. These results suggest that LDR at25mGy in renal region once a week for8weeks, as a novel, noninvasive, profoundly effective, safe and convenient therapeutic intervention method, is the optimal condition to protect the kidney from diabetes.Conclusions:1. LDR prolongs the progression of DKD at the early stage.2. The key points to get the greatest advantage of LDR include the dose, frequency and mode. Our results suggest that renal region exposure of25mGy weekly for8weeks is the optimal condition of LDR to protect the kidney from diabetes.3. There should be a low-dose threshold, and the protective effect will be induced in a dose-dependent manner from12.5mGy to50mGy until the protective effect reaches the maximal level when the dose is optimal, but the protective effect is not inducible if the dose is too low.4. The protective effect of LDR is ififluenced by accumulated doses, and the further elevated radiation dose will increase risks of toxic side effects. In addition, the higher the single dose is, the earlier and the more severe the toxic side-effects appear.5. The protective effect of LDR lasts more than4weeks after cessation of LDR for4weeks.6. LDR protects the kidney from diabetes by activation of antioxidants.7. The protective effect of LDR on blood glucose is displayed after a longer time.In summary, LDR had a profound beneficial effect on DKD as a novel, noninvasive, safe, convenient therapeutic intervention method, and is very practical and significant in the basic and clinical research.