Therapeutic Effects Of Zinc On Diabetic Nephropathy

Diabetes mellitus (DM) is a clinical syndrome that is hypofuction of islet induced bypathogenic factors included genetic factors and environmental factors. Insulin deficiencyresulting from a defect in insulin secretion, insulin action, or both, in turn leads to chronichyperglycaemia with disturbances of carbohydrate, fat and protein metabolism. As the diseaseprogresses tissue or vascular damage ensues leading to severe diabetic complications, whichwill finally lead to the dysfuction and failure of organs and become the main cause ofmorbidity and mortality. The World Health Organization states that worldwide the number ofindividuals with diabetes is expected to surpass550million by2030. This will bring a heavyfinancial burden to society and family. How to effectively treat diabetes and its complicationswill be an urgent clinical problem need to conquer.Diabetic nephropathy (DN) is the most common microvascular complication of diabetesmellitus. It is a leading cause of end-stage renal disease and a contributor to significantmorbidity and mortality in patients with diabetes. Several mechanisms are thought to beinvolved in the pathogenesis of diabetic nephropathy and its complications, all of themoriginating from hyperglycemia. It induces activation of protein kinase C, increasedproduction of advanced glycosylation end products, and diacylglycerol synthesis.Inflammation, oxidative stress and fibrosis may be activated by hyperglycemia in kidneytissues which eventually leads to basement membranes thickening, extracellular matrixaccumulation and glomerular sclerosis. All these changes plays an important role in thedevelopment and progression of DN. Increasing the sensitivity of insulin signal, andimproving glucose metabolism become a clinical hotspot recently in dealing with diabetickidney disease.Zinc (Zn) is a trace element that plays a pivotal role in the proper functioning of manyenzymes and transcription factors. Zn has been used clinically in the treatment of severaldiseases. Its low toxicity profile makes it possible to use in pediatric patients. Diabeticpatients are often Zn deficient owing to elevated urinary Zn excretion,decreased intestinal Znabsorption, and are stricted diet. So Zn supplementation may be beneficial for the treatment ofDN. Recently, meta-analysis and systematic review of clinical data showed the beneficial effects of Zn supplementation for diabetic patients. Human study proves that Znsupplementation reduces albumin excretion in micro albuminuric type2diabetic patients.However, the mechanism by which zinc protects the kidney from diabetes remains unknown,so we conducted a series of research.Firstly, we examined whether Zn can provide a therapeutic effect against DN and thepossible mechanism of it using the OVE26type1diabetic mouse model. We have examinedthe renal pathological and functional changes, Akt-mediated molecules related to metabolism,MT and Akt negative regulators in the kidney of OVE26type1diabetic mice. Because of theimportant role of Akt2in insulin-mediated glucose metabolism, We then examined whetherthe therapeutic effect of Zn on the diabetic kidney is dependent on Akt2using an Akt2-KOmouse model. Finally, we examined if MT is required for Zn stimulation of Akt and itsdownstream pathways by using mice with an MT gene deletion (MT-KO). The results ispresented:(1) We found ACR continually increase in both the DM group and the DM/Zn group, butit was slightly lower in DM/Zn mice than in DM mice at6months. The renal fibroticresponse, inflammation and oxidative damage were significantly increased in DM mice, butwas significantly prevented by Zn treatment. The above results have shown Znsupplementation can significantly improve diabetes-induced renal functional and pathologicalchanges in OVE26and Akt2-KO diabetic models;(2) We demonstrated that decreased renal Akt phosphorylation along with diabetesinduced pathological changes in the kidney which were significantly attenuated by Zntreatment, such that Akt phosphorylation in both OVE26and Akt2-KO diabetic mouse modelswas almost completely preserved. Preservation of renal Akt phosphorylation by Zn treatmentwas associated with normal GSK-3βphosphorylation and HKII expression in both OVE26andAkt2-KO diabetic mice.(3) Zn treatment prevents diabetic upregulation of the Akt negative mediators PTEN,PTP1B, and TRB3in OVE26and Akt2-KO diabetic models, but had no effect under normalconditions.(4) By detecting renal functional, pathological changes and Akt-mediated moleculesrelated to metabolism in the kidney tissue of Akt2-KO mouse, we found that deletion of theAkt2gene had no effect on Zn’s ability to provide renal protection against diabetes-inducedfunctional and pathologic changes; furthermore, deletion of the Akt2gene had no effect onZn-induced stimulation of Akt-mediated metabolic signaling. we draw the conclusion that zn protection against diabetes-induced renal damage is independent of Akt2.(5) We also checked phosphorylation of renal Akt and GSK-3βas well as the expression ofHKII in MT-KO mice after Zn supplementation1month, and found that Zn-inducedstimulation of Akt-related metabolic signaling is MT dependent, at least under normalphysiological conditions.In summary, this study shows that Zn stimulation of Akt-mediated renal glucosemetabolism improves renal functionin OVE26and Akt2-KO diabetic models.We furthershowed that the preservation of Akt-mediated metabolic signaling by Zn was not dependenton Akt2, but was dependent on MT. The preservation of Akt-mediated metabolic signalingunder diabetic conditions may be associated with Zn suppression of Akt negative regulators,PTEN phosphorylation, and PTP1B, aswellas TRB3, which needs further investigation.Considering that diabetic patients are often Zn deficient owing to elevated urinary Znexcretion, decreased intestinal Zn absorption, and are stricted diet, this study suggests thatregularly monitoring Zn levels in diabetic patients, as well as adequate Zn supplementation inpatients whose Zn levels are low, would be very important in mitigating the development ofdiabetic nephropathy.Innovations:(1) We demonstrated that Zn supplementation can significantly improve diabetes-inducedrenal functional and pathological changes in OVE26and Akt2-KO diabetic models and havethe protective effects on DN.(2) We elucidated the possible mechanisms of the protective effects of Zn supplementationon DN. The therapeutic effect of Zn treatment on the diabetic kidney is associated with thestimulation of MT expression and Akt-mediated metabolic signaling. Preservation ofAkt-mediated metabolic signaling by Zn treatment may be associated with Zn-mediatedsuppression of Akt negative regulators PTEN phosphorylation and PTP1B and TRB3expression, under diabetic conditions.(3) We demonstrated that deletion of the Akt2gene had no effect on Zn’s ability toprovide renal protection against diabetes-induced functional and pathologic changes;furthermore, deletion of the Akt2gene had no effect on Zn-induced stimulation of Akt-mediated metabolic signaling. zn protection against diabetes-induced renal damage isindependent of Akt2.(4) We elucidated that Zn-induced stimulation of Akt-related metabolic signaling is MT dependent, at least under normal physiological conditions.