High blood sugar may blunt the protective benefits of FXR for the survival of renal medullary collecting duct cells in response to hypertonic stress

Abstract

AbstractBackgroud: Diabetic nephropathy is the most common renal complication of diabetes and the leading cause of end-stage renal disease. many factors lead to the occurrence of this disease. However, little attention has been paid to the effect of water deficiency on DN. This study focused on the effect of dehydration on renal injury in diabetes mellitus. Methods Diabetic and non-diabetic mice were deprived of water every other day for a total of 16 weeks. The effects of water deficiency on kidney of diabetic and non-diabetic mice were analyzed by physiological indexes, biochemical tests, pathology and the expression changes of proteins. Finally, we verified the important role of farnesoid X receptor transcription factor(FXR) in renal injury caused by dehydration once again through the study of FXR knockout mice. Results Our animal studies confirmed that kidney injury was more obvious in diabetic mice after water deprivation.Diabetic mice had increased urine volume and serum concentrations of creatinine after dehydration, pathological injury of renal medulla was also observed. We further demonstrated that glycoprotein 91/ aquaporin 2 expression increased in renal medulla under water deficiency, especially under high blood serum glucose concentrations. At the same time, in high sugar environment, dehydration caused overexpression of FXR and tonicity-responsive enhancer-binding protein(TonEBP), which led to oxidative stress damage to the renal medulla. However, this oxidative stress damage was weakened after FXR knockout. Conclusions Hypertonic conditions in high glucose environments promote overexpression of FXR. It binds TonEBP in the renal medulla, thus leading to excessive oxidative stress damage and ultimately to renal medulla damage.