| Objective:Acute kidney injury (AKI) is one of the most common clinical problems in critically ill patients, sepsis is the primary cause of AKI. The patients with both sepsis and AKI have an especially high mortality rate. So, the exploration of protective treatment about sepsis-induced AKI has important clinical significance. Melanocortin4receptor (MC4R) plays an important role in energy metabolism, feeding, sexual function and cardiovascular function. It is reported that selective activating MC4R can activate the cholinergic anti-inflammatory pathway, then significantly inhibit the inflammation progress of severe acute pancreatitis rats and protect the pancreatic tissue. It hasn’t been reported that when sepsis-induced AKI whether it is effective to use selective activating MC4R to activate cholinergic anti-inflammatory pathway, then inhibit inflammation response to protect kidney of patients with sepsis. This experiment establishes the model of sepsis by cecal ligation and puncture (CLP), then observes the influence of kidney tissue induced by sepsis, and explores establishment of animal model about sepsis-induced AKI. Intervening with selective activating MC4R in rat model of sepsis-induced AKI, then observes the influence of kidney tissue, and elaborate the protective mechanism of selective activating MC4R on sepsis-induced AKI, providing theoretical and experimental basis for the clinical prevention and treatment of sepsis-induced AKI.Methods:The experiment established sepsis model by cecal ligation and puncture.(1) Male Sprague-Dawley rats were randomly divided into sham operation group (Sham group) and cecal ligation and puncture group (CLP group),18rats for each group. Both groups were sampled at6h,12h and24h after the operation, then observe the levels of heart rate (HR) and mean arterial blood perssuer (MABP), the expressions of tumor necrosis factor-α (TNF-a) and interleukin-6(IL-6) in serum, the levels of creatine (CRE) and blood urea nitrogen (BUN) in serum, the change of kidney structural, the expression of high mobility group box1protein (HMGB1) mRNA and the activation of nuclear factor-KB (NF-κB) in kidney tissue (2) Male Sprague-Dawley rats were randomly divided into sham operation group (Sham group), sham operation+Ro27-3225treatment group (Sham+Ro27group), cecal ligation and puncture group (CLP group) and cecal ligation and puncture+Ro27-3225treatment group (CLP+Ro27group),6rats for each group. All the four groups were sampled at24h after the operation, then observe the levels of HR and MABP, the levels of CRE and BUN in serum, the change of kidney structural, the expression of HMGB1mRNA and the activation of NF-κB in kidney tissue.Results:(1) Compared with time-matched Sham group, HR and MABP of CLP group were significantly higher at6h and12h (p<0.01), MABP of CLP group at24h was lower (p<0.01); the expressions of TNF-a and IL-6in serum of CLP group were significantly higher at6h and12h (p<0.01), then decreased to the level of sham group at24h (p>0.05); the level of BUN in CLP group was increased at6h,12h and24h (p<0.05and p<0.01), the level of CRE was significantly increased at24h (p<0.01); the expression of HMGB1mRNA in kidney tissue of CLP group was higher at12h and significantly higher at24h (p<0.01); the nuclear positive rate of NF-κB p65in kidney tissue of CLP group was higher at6h, and significantly higher with further infection of sepsis; corpuscle and renal tubular with regular shapes in each group of Sham group, the damage of CLP group consisted mainly in wrinkled corpuscles, enlarged filtration chambers, the wrinkled corpuscle was increased and epithelial cell of kidney tubules stenosis swelling and necrosis appeared with further infection of sepsis.(2) HR and MABP of Sham+Ro27group were significantly lower than Sham group (p<0.01), MABP of CLP group was lower than Sham group (p<0.01), MABP of CLP+Ro27group was higher than CLP group (p<0.01); the level of CRE and BUN in serum of CLP group were significantly higher than Sham group (p<0.01), the level of CRE and BUN in serum of CLP+Ro27group were lower than CLP group (p<0.01); the expression of HMGB1mRNA in kidney tissue of CLP group was significantly higher than Sham group (p<0.01), the expression of HMGB1mRNA in kidney tissue of CLP+Ro27group was lower than CLP group (p<0.01); the nuclear positive rate of NF-κB p65of CLP group was significantly higher than Sham group (p<0.01), the nuclear positive rate of NF-κB p65of CLP+Ro27group was lower than CLP group (p<0.01); corpuscle and renal tubular with regular shapes of Sham group and Sham+Ro27group, the damage of CLP group consisted mainly in wrinkled corpuscles, enlarged filtration chambers, and swelled epithelial cell of kidney tubules stenosis, the damage of CLP+Ro27group was lighter than CLP group, the number of wrinkled corpuscles decreased, edema and inflammatory cell infiltration also improved.Conclusions:Using the method of cecal ligation and puncture can copy rat model of sepsis-induced AKI successfully, making structural and functional change of kidney in the rats, increaseing the expression of HMGB1mRNA and nuclear positive rate of NF-κB p65in kidney tissue. Selective activating MC4R could protect the structure and function of kidney with sepsis-induced AKI, and inhibit the increasing of expression of HMGB1mRNA and nuclear positive rate of NF-κB p65in kidney tissue... |
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