| Chronic kidney disease(CKD)is a common clinical disease with an incidence rate of 11-13%.With the progressive loss of nephron,patients are likely to progress to end stage renal disease(ESRD).After ESRD,all patients need renal replacement therapy.Peritoneum dialysis(PD)has many advantages,such as flexible operation,low cost in treatment,easy to return to society,and its clinical prognosis is no less than that of hemodialysis(HD),so it has become one of the most important renal alternative treatment methods.Matrix metalloproteinase 7(MMP7)is a secreted,zinc and calcium dependent endopeptidase.Structurally,MMP7 is one of the smallest matrix metalloproteinases,generally in the form of inactive zymogens;after activation,the N-terminal pro peptide segment is removed by protein hydrolysis,and finally the active enzyme is formed.The main function of MMP7 is to destroy the extracellular matrix by digesting casein,gelatin,fibronectin and proteoglycan;MMP7 can also play a role in the exfoliation of E-cadherin,promote the release of tumor necrosis factor alpha(TNF-α)and activate other proteases.MMP7 is a potential participant in many biological processes,such as tissue remodeling,apoptosis and inflammation.Some studies have shown that matrix metalloproteinases such as matrix metalloproteinase 2(MMP2)and matrix metalloproteinase 9(MMP9)are involved in the induction of peritoneal angiogenesis and affect solute transport in peritoneal dialysis.However,it is not clear whether MMP7 has any effect on peritoneal dialysis.Our study found that MMP7 has rich expression in peritoneal dialysis fluid of ESRD patients,and its concentration is negatively related to the ultrafiltration volume of peritoneal dialysis,suggesting that MMP7 may affect the ultrafiltration of peritoneal dialysis.Aquaporin-1(AQP1)is the main channel protein regulating the rapid flow of water molecules into and out of cells.It is closely related to the removal of water by peritoneal dialysis.Many studies have shown that AQP1 has a large number of expression in peritoneal tissue,and the peritoneal mesothelium composed of monolayer peritoneal mesothelial cells is an important anatomical structure in peritoneal dialysis process,so we pay attention to peritoneal mesothelial cells.MMP7 stimulated peritoneal mesothelial cells:compared with the control group,the expression of AQP1 in MMP7 stimulated cells increased significantly;compared with the change of cell diameter after incubation in hypertonic or hypotonic solution for 1 min,the change of cell diameter in MMP7 stimulated peritoneal mesothelial cells was faster,suggesting that MMP7 upregulated AQP1 to increase the permeability of cells.Next,we want to further study the regulatory mechanism.Some studies have shown that the phosphorylation of some molecules in MAPK(mitogen activated protein kinase)pathway has a bidirectional regulatory effect on AQP1.After stimulation of MMP7,we found that the phosphorylation level of p38,JNK(c-Jun N-terminal kinase)and ERK(extracted regulated protein kinases)increased,suggesting that MMP7 upregulated AQP1 by activating MAPK pathway.Next,the expression of AQP1 in peritoneal mesothelial cells was detected when MMP7 and p38,JNK,ERK inhibitors were added in the supernatant of cultural cells at the same time,we found that only ERK inhibitor(U0126)could prevent the upregulation of MMP7 on AQP1,indicating that MMP7 upregulated the AQP1 expression of peritoneal mesothelial cells by promoting ERK phosphorylation.In conclusion,we found that MMP7,which is highly expressed in dialysate,up-regulated AQP1 expression on peritoneal mesothelial cells by activating ERK in MAPK pathway to increase cell permeability,so that peritoneal water reabsorption increased and ultrafiltration in the peritoneal dialysis reduced,ultimately ultrafiltration failure(UFF)happened.UFF is a common cause of peritoneal dialysis failure,which often increases the rate of hospitalization and mortality.The results will provide new insights and theoretical basis for clinical prevention and treatment of UFF. |
PDF Full Text Request