The Mechanism Of Estrogen Improves Diabetes-induced Kidney Injury Through AMPK α1

IntroductionsClinical trials proved that gender was an independent risk factor of diabetic kidney disease,the prevalence of DKD was significant lower in female compared by male,estrogen replacement therapy could delay the progression of CKD.Female mice were resistant to both obesity-and diabetes-induced kidney injury.Reduction in renal Adenosine5’-monophosphate(AMP)-activated protein kinase(AMPK)activity is associated with diabetes-and obesity-induced kidney injury which is ameliorated by AMPK stimulation in male mice.We hypothesized that AMPK regulation of toxic metabolites may contribute to sex related protection against kidney injury in diabetic female mice.MethodsWe employed 12-16 weeks old Kidney Tubule specific AMPKα1knock out(KTα1KO)mice and their WT male and female mice.Diabetes was established by high fat diet(HFD)followed by streptozotocin(STZ)injection.MCT cells were used to explore the mechanism of estrogen protection from HG in vitro.Immunoblot analysis and mass spectrometry were used to detect the signaling changes and metabolites changes.ResultsDiabetes induced systolic hypertension and renal fibrosis along with increase in urinary adenine level in WT and KTα1KO male mice whereas wild type female mice were resistant to diabetes-induced changes.Importantly,KTα1KO female mice with diabetes had a similar degree of renal injury and fibrosis as did the male mice.Urine adenine levels were low in wild type female mice with diabetes but significantly increased in female KTα1KO with diabetes.Besides,ACR was correlated with adenine concentration in mice.iabetes could increase the expression of adenine synthesis enzyme –MTAP,and this could be attenuated by AMPK activator.In vitro,adenine reduced the AMPK activity and activated m TOR/S6 K pathway in MCT cells and could be reversed by AMPK activator.ConclusionsOur studies show that the mechanism by which female mice resist diabetes related kidney injury is by maintaining intact AMPK activity.Adenine synthesis could be up-regulated and engage the suppression of AMPK activity in diabetes.