The Role Of PGRN In Sepsis Induced Acute Kidney Injury

Sepsis is a complex clinical syndrome characterized by systemic inflammatory response induced by infection. Sepsis often leads to systemic tissue damage and multiple organs dysfunction. Acute kidney injury (AKI) is one of the most common complication of sepsis, it not only increases the complexity of the disease and nursing cost, also causes the high risk factors of death. The pathological mechanism of septic AKI is very complex, involving hemodynamic change, imbalance of endothelial cells, inflammatory cells infiltration of renal parenchyma, thrombus of glomerulus and renal tubules dysfunction induced by necrotic cells and debris.Progranulin (PGRN) is a secrete growth factor, and highly expresses in the epithelial cells and certain types of nerve cells and macrophages, also widely expresses in other tissue and cell types, including skeletal muscle, adipose tissue, hematopoietic cells, cartilage cells and immune cells, etc. PGRN has many physiological functions, it not only maintains and regulates the development of normal tissue and proliferation, regeneration and host defense, but also is involved in the process of various types of disease, including autoimmune diseases, cancer and neurodegenerative diseases, etc. In recent years, it has caught extensive attention that PGRN plays a critical role in inflammation. Recent literatures have reported that PGRN plays a protective role in AKI induced by renal ischemia/reperfusion model. But the role of PGRN in sepsis induced acute kidney injury has not yet been explored.In this study, we used two kinds of common model of sepsis, lipopolysaccharides (LPS) injection and cecum ligation and perforation (CLP), to investigate the effects of PGRN on acute kidney injury induced by sepsis.Objective:To investigate the effects of PGRN on acute kidney injury induced by sepsis.Methods:To detect the level of PGRN of wild type (WT) mice in sepsis model, sepsis animal models are established by injection of LPS and CLP in mice, and blood and kidney tissue are collected from mice at 6 h and 24 h after injection or surgery. Real-time quantitative RT-PCR is employed to detect the mRNA level of PGRN in renal tissue, Western blot and immunohistochemistry staining are used to detect PGRN protein expression, and ELISA is carried out to detect the level of PGRN in renal tissue homogenate. To explore the function of PGRN in septic AKI, wild type (WT) and PGRN deficient (Grn-/-) mice are used to establish sepsis models, or WT mice are administrated with recombinant PGRN (rPGRN) at 2h before LPS injection or CLP. Then serum creatinine (Scr) and blood urea nitrogen (BUN) of mice are determined by blood biocheminstry assay, kidney tissue damages are revealed by hematoxylin and eosin staining (H&E), neutrophils and macrophages infiltration in kidney are determined by immunohistocheminsty staining, and the mRNA levels of inflammatory cytokines in kidney tissue are detected by using real time quantitative RT-PCR. To study the role of PGRN in apoptotic death of renal tubular epithelial cells TUNEL labeling is carried out and the levels of apoptosis-related protein are detected by Western blot.Results:In both of the LPS and CLP models, we found that the protein and mRNA levels of PGRN in kidney of septic mice were elevated compared with the normal mice. Comparing with septic WT mice, septic Grn-/- mice showed more elevated Scr and BUN levels; H&E staining showed that renal injury of Grn-/- mice is more serious than that of WT mice; immune cells infiltration, mRNA expression of inflammatory cytokines and apoptotic death of renal tubular epithelial cells in kidney from Grn-/- mice were enhanced compared with WT mice. Oppositely, injection with rPGRN resulted in reduced Scr and BUN levels compared with PBS injected septic mice. rPGRN also attenuated sepsis induced renal damage, inflammatory response and apoptotic death of renal tubular epithelial cells.Conclusions:PGRN levels are elevated in kidney and blood of septic mice. PGRN deficiency results in more severe AKI induced by sepsis, and rPGRN administration displays protective role in septic AKI.In this study, we proved the protective effect of PGRN on sepsis-related AKI by using sepsis animal models induced by LPS injection and CLP in WT and Grn-/- mice or administration with rPGRN. PGRN-mediated anti-inflammation and anti-apoptosis contribute to the renal protective role of PGRN. This study provides a theoretical basis for the clinical prevention and treatment of sepsis and sepsis-related AKI.