Mechanism Of Endoplasmic Reticulum Stress Leading To Renal Injury In Rats With Intermittent Hypoxia And Intervention Of Losartan

Objective: An intermittent hypoxia(IH)rat model was established to simulate the nocturnal hypoxia/reoxygenation pathophysiological process in patients with obstructive sleep apnea hypopnea syndrome(OSAHS),and to explore the relationship between renal injury and the expression of Caspase-12 mRNA,JNKmRNA and CHOPmRNA in IH rats,and the intervention effect of losartan.To present new diagnostic ideas and theoretical basis for clinical prevention and treatment of OSAHS-induced renal injury.Methods: Choose 60 SPF grade healthy male SD rats,randomly divided into four groups(15 for each group).Group A: control group,free activities;Group B:IH group,placed in intermittent hypoxic chamber with free activities;Group C: IH+losartan group,Losartan 30mg/kg was injected intraperitoneally daily and placed in intermittent hypoxic chamber with free activities;Group D: IH+saline group,the same dose of saline was injected intraperitoneally daily as a balanced control and placed in intermittent hypoxic chamber with free activities.The model was made 8 hours a day(09:00-17:00)for 6 weeks.After 6 weeks of modeling,the serums of rats in each group were taken to detect the renal function.HE staining was used to observe the histomorphological changes of the kidney;transmission electron microscopy was used to observe the ultrastructural changes of the kidney;TUNEL was used to detect the apoptotic index of renal cells;rt-PCR was used to detect the expression of Caspase-12 mRNA,JNKmRNA and CHOPmRNA in the kidney.Results: 1.BUN in group B and group D were significantly higher than those in group A(both P < 0.01).BUN in group C was lower than that in group B and D(both P < 0.05).CREA in group B and group D were higher than those in group A(P < 0.01;P < 0.05).There was no significant difference in CREA levels between groups B,C and D(P > 0.05).2.HE staining showed normal kidney in group A;the renal tubular epithelial cells in group B and D were highly swollen and the lumen had different degrees of stenosis;some proximal convoluted tubular epithelial cells in group C were slightly swollen and the lumen was not obviously narrowed.3.Transmission electron microscopy showed normal kidney in group A;microvilli on the surface of renal tubular epithelial cells were sparse,exfoliated,nucleus pyknosis and organelle lysis in group B and D;Group C: A few of microvilli on the free surface of renal tubular epithelial cells were prostrate and sparse,a small number of nuclei were atypical,and organelles were slightly swollen.4.TUNEL showed that the apoptosis index of renal cells in group B and group D were significantly higher than group A(both P <0.01).Compared with group C,the apoptosis index in group B and group D were significantly increased(both P < 0.01).5.Pearson correlation analysis showed that apoptotic index of renal cells was positively correlated with BUN(r = 0.831,P < 0.01)and CREA(r = 0.581,P < 0.01).6.rt-PCR showed that the Caspase-12 mRNA,JNKmRNA and CHOPmRNA expression in group B and D were significantly higher than those in group A(all P < 0.01);after the intervention of losartan,the expression of Caspase-12 mRNA in group C was lower than that in group B and D(P < 0.01;P < 0.05);there was no significant difference in the expression level of JNKmRNA between group B,C and D(P > 0.05);the expression level of CHOPmRNA in group C was significantly lower than that in group B and D(both P < 0.01).Conclusions: 1.IH may induce apoptosis of renal tubular epithelial cells in rats,resulting in ultrastructural changes of renal tissue and impairment of renal function.2.IH may induce apoptosis of renal tubular epithelial cells by activating the expression of Caspase-12 mRNA,JNKmRNA and CHOPmRNA in ERS apoptotic pathway.3.Losartan may play a protective role in the kidney by inhibiting the expression of Caspase-12 mRNA and CHOPmRNA in ERS apoptotic pathway.