| Diabetes Mellitus (DM) is a chronic multifactorial metabolic disorder resulteddue to the altered homeostasis between glucose production and its metabolism. DM ismainly characterized by hyperglycemia, altered lipid metabolism ascribed due to theunsubstantial amount of insulin production by the β-cells, secretion or both andinsulin resistance, oxidative stress, and inflammation. With the rapid economicdevelopment, elevated standard of living, dietary shift, lifestyle alterations, and aging,DM has become an important public health problem worldwidely, which is estimatedto be the third most challenging disease threatening public health after malignanttumors and cardiocerebral vascular diseases. It has been estimated that the globalnumber of individuals with diabetes will double from151million in2000to553million in2030among adults aged≥20years. Diabetes and its complications alsoresult in significant economic burden among individuals, families, and society. Howto effectively prevent diabetes and its complications has been a hot topic of medicalfield, which need to conquer.Diabetes can affect many organ systems throughout the body (e.g., renal system,nervous system, and eyes) and can lead to serious complications over time. Diabeticnephropathy(DN) as one of microvascular diseases is not only the commoncomplication of diabetes and also the main cause of the mortality for diabetic patients.Although glucose control, blood pressure, lipid lowering, and the blockade of therenin-angiotensin system were used for the treatment of diabetic patients, thedevelopment and progression of nephropathy in the patients with diabetes remainsunpreventable. DN is distinguished histologically by glomerular hypertrophy,thickening of the glomerular basement membrane, expansion of the mesangial matrixand final glomerulosclerosis. Oxidative stress mediates the deleterious effects ofdiabetes on renal tissue function. The high glucose induction of reactive oxygenradicals both interrupts microvascularity and promotes the accumulation of themesangial matrix. Therefore, How to modulate oxidase activity and anti-oxidant capacity in order to prevent or delay the development and progression of DN isurgently needed.Zinc (Zn) is one of the necessary trace elements within cells and is necessary for abroad range of physiological processes. Zinc is an integral component of proteinsinvolved in cell structures and the stabilization of cell membranes. It functions tomaintain the structural integrity of as many as3000transcription factors in the humangenome and is essential for the biological activity of more than300zincmetalloenzymes.In diabetes, it always present with zinc deficiency. In addition to inadequatedietary zinc intake, deficiency may result from impaired absorption or resorption orincreased excretion of zinc; in diabetes, increase endogenous zinc losses. Zinc isimportant in insulin action and carbohydrate metabolism. Oxidative stress plays animportant role in the pathogenesis of diabetes and its’complications. Zinc is astructural part of key anti-oxidant enzymes such as superoxide dismutase, and Zincdeficiency impairs their synthesis, leading to increased oxidative stress. However, theeffects ofdifferent concentrations of zinc on diabetic nephropathy and theirmechanism remain unclear, so we conducted the following research.FVB male mice aged of8weeks were injected intraperitoneally with MLD-STZat50mg/kg daily for5days. One week after the last injection of STZ, whole-bloodglucose obtained from mouse tail-vein was measured with a complete blood glucosemonitor. Blood glucose levels higher than16.7mmol/L were considered ashyperglycemic. Diabetic and age-matched control mice were treated with the differentconcentration of zinc diets for3months, which is successfully established differentzinc content of type1diabetes kidney disease animal model through the detection ofzinc content. Then we utilized the western blot, Histopathologic examination andother experimental methods to detect the level of renal function, pathological changesof the renal, oxidative damage, inflammation, fibrosis and apoptosis will be detectedin order to know the protection of zinc in diabetic nephropathy, which is in order toexplore the effects of different concentration of zinc on diabetic nephropathy in mice.After that, we detected the level of Nrf2and other anti-oxidant factors to understandthe possible mechanism of the effects of different concentration of zinc on diabeticnephropathy in mice. Finally, we detected the level of AKT, GSK-3β and Fyn inorder to clear the effect of zinc on the activation of AKT and its downstream pathway, which is contribute to understand the relationship of Zinc, AKT and Nrf2. The resultsare presented:1. Feed with the different concentrations of zinc diets didn’t affect the level ofblood glucose, body weight and the ratio of kidney and body weight in STZ-induceddiabetic mice.2. The low zinc intervention on diabetic mice significantly increases themortality rate, ACR values and urea nitrogen values, while the normal and high zincinterventions can improve the changes.3. Compared with the corresponding control group, the expression of oxidativedamage index SOD1and SOD2is down-regulated in diabetic groups. Instead, theexpression of inflammation index PAI-1and TNF-α, and the expression of fibrosisindex CTGF and TGF-β1are up-regulated in diabetic groups. In these diabetes groups,the low zinc intervention can aggravate the injury, while the normal and high zincinterventions can improve the changes, especially through the high zinc intervention.4. Through PAS staining, we found that diabetic mice aggravate the glomerularhypertrophy and the expansion of the mesangial matrix. Through electron microscope,micrographs from diabetic mice disclosed thickening of glomerular basementmembrane, local foot process effacement and increased swollen mitochondria intubular epithelial cells. The low zinc intervention might aggravate the pathologicalchanges, while the normal and high zinc interventions might improve them partly.5. Compared with the corresponding control group, diabetic mice downregulatedthe expression of Nrf2and its downstream factor NQO1, SOD1, SOD2. In thesediabetes groups, the low zinc intervention can downregulate the expression of themfurthermore, while the normal and high zinc interventions can upregulate theexpression of them.6. Compared with the corresponding control group, diabetic mice downregulatedthe phosphorylation level of AKT and GSK-3β. In these diabetes groups, the low zincintervention can downregulate the phosphorylation level of them furthermore, whilethe normal and high zinc interventions can upregulate the phosphorylation level ofthem.7. Compared with the corresponding control group, diabetic mice increase thenuclear translocation of Fyn in order to export Nrf2to the cytosol where Nrf2isdegraded. In these diabetes groups, the low zinc intervention can increase the nuclear translocation of Fyn furthermore, while the normal and high zinc interventions canprevent.According to the above experimental results, we draw the following conclusion:Zinc deficiency enhances the damage of diabetic nephropathy to some extent. Tosupply with the normal and high concentration zinc can partly protect the disease ofdiabetic nephropathy, which is achieved possiblely by upregulating the expression ofNrf2and its downstream factor NQO1, SOD1, SOD2. The one of the possiblemechanisms is as follows. The translocation of Fyn into the nucleus is partly mediatedby GSK-3β that is active in dephosphorylated form and inactive in phosphorylatedform. Zn upregulated the expression of Akt phosphorylation and, consequently,dowmregulated the expression of GSK-3β phosphorylation, can result in the reductionin Fyn nuclear translocation to export Nrf2to the cytosol. In short, Zn may induced asignificant decrease in Fyn expression in nuclear and an increase in cytosolic, alongwith the up-regulation of Akt and GSK-3βphosphorylation, and Nrf2, NQO1, SOD1,SOD2expression, in order to partly protect against diabetes-induced renal damage. |
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