The Protective Effects And Mechanism Of Ghrelin In Sepsis–Induced Acute Kidney Injury

Objective:In this study,sepsis complicated by AKI was induced by lipopolysaccharides(LPS)in rats.The renal protective effects and mechanism of Ghrelin in this model,as well as the role of vagus nerve in this process,were investigated.This may provide news ideas in the treatment of sepsis-induced AKI.Methods:Male Wistar rats were randomly assigned into one of the following 5 groups(16 rats/group): Sham LPS group(group A),LPS-induced AKI group(group B),Ghrelin-treated LPS-induced AKI group(group C),vagotomized LPS-induced AKI group(group D)and Ghrelin-treated vagotomised LPS-induced AKI group(group E).Scr was measured by sarcosine oxidase method and Bun by urease method.Serum PCT,TNF-α,MPO,VCAM-1,Ghrelin,and renal TNF-α,MPO levels were measured by Elisa method.The gene and protein expression of Ghrelin,GHS-R1α mRNA,and VCAM-1 in renal homogenates were measured by RT-PCR and Western Blot.Results:1.The blood pressure(represented by mean arterial pressure)of rats in group A had no significant changes compared with that before the experiment(P>0.05),while the blood pressure of the other four groups after the experiment was significantly lower than that before the experiment(P<0.05).Compared with group A,the blood pressure of rats in groups B,C,D and E was significantly lower after the experiment(P<0.05).The blood pressure of group C was significantly higher than that of group B(P<0.05).The blood pressure of rats in group D and group E were significantly lower than that of group C(P<0.05).2.The loss of body weight was significantly increased in the other four groups than in group A(P<0.05).Compared with group B,the loss of weight of group C was significantly decreased(P<0.05).The loss of weight of group D and E were significantly increased than that of group C(P< 0.05).3.Compared with group A,the urine volume in the other four groups was significantly decreased(P<0.05),while the blood urea nitrogen,serum creatinine,and procalcitonin levels were significantly higher(P<0.05).The urine volume of the rats in group B was significantly decreased while the blood urea nitrogen,serum creatinine and procalcitonin were significantly increased than that in group C(P<0.05).Compared with group C,the urine volume of rats in groups D and E was significantly decreased(P<0.05),and the levels of blood urea nitrogen,serum creatinine and procalcitonin were significantly higher(P< 0.05).4.Light microscopy(HE staining)showed no obvious pathological changes in group A.There were varying degrees of renal tubular epithelial cell degeneration,brush border detachment,cell debris in the lumen,as well as some renal tubules atrophy,renal interstitial edema in group B,D,and E.The pathological changes in group C was much better.According to the standard of renal injury,the scores in group B,C,D and E were significantly higher than those in group A(P<0.05).Compared with group B,the scores of group C were significantly lower(P<0.05).The scores of renal injury in group D and E were significantly higher than those in group C(P<0.05).5.Compared with group A,serum TNF-α,MPO and VCAM-1 levels of the other four groups were significantly higher(P<0.05).TNF-α,and MPO levels,VCAM-1 gene expression in rats kidney tissue were also increased significantly(P<0.05).The above indexes in group C were significantly decreased than those in group B(P<0.05).Compared with group C,the above indexes in group D and E were significantly higher(P<0.05).VCAM-1 protein expression in rats kidney tissue of group C were slightly increased than in group A(P>0.05).The VCAM-1 protein expression was significantly upregulated in group B,D,and E than those in group A and C(P< 0.05).6.The Ghrelin level in serum were significantly increased in group B,C,D,and E than in group A(P<0.05).The levels of Ghrelin in group C and E were significantly increased than those in group B and D(P<0.05).The gene and protein expression of Ghrelin and GHS-R1α were significantly upregulated in the kidney of group B and C than in group A(P<0.05).Compared with group B,the gene and protein expression of Ghrelin and GHS-R1α in group C were significantly up-regulated(P<0.05),the gene and protein expression of Ghrelin and GHS-R1α in groups D and E were significantly decreased(P<0.05).The gene and protein expression of Ghrelin and GHS-R1α of group D and E were significantly decreased than that of group C(P <0.05).Conclusion:1 Ghrelin has anti-inflammatory effects in sepsis-induced AKI rats.2 Ghrelin has renal protective effects in sepsis-induced AKI rats.3 The anti-inflammatory and renal protective effects of Ghrelin were disappeared after vagotomy,suggesting that the expression of kidney Ghrelin receptor may be innervated by the vagus nerve.