Abstract
Substance P (SP), an injury-inducible messenger that mobilizes bone marrow stem cells and modulates the immune response, has been suggested as a novel target for therapeutic agents. We evaluated the role of SP as an immune cell modulator during the progression of renal ischemic/reperfusion injury (IRI). Unilateral IRI induced the transient expression of endogenous SP and the infiltration of CCR7+ M1 macrophages in injured kidneys. However, SP altered the intrarenal macrophage polarization from CCR7+ M1 macrophages to CD206+ M2 macrophages in injured kidneys. SP also modulated bone marrow-derived neutrophils and mesenchymal stromal cells after IRI. SP treatment for 4 weeks starting one week after unilateral IRI significantly preserved kidney size and length and normal tubular structures and alleviated necrotic tubules, inflammation, apoptosis, and tubulointerstitial fibrosis. The beneficial effects of SP were accompanied by attenuation of intrarenal recruitment of CD4, CD8, and CD20 cells and abnormal angiogenesis. The immunomodulatory effect of SP suggested that SP could be a promising therapeutic target for preventing the progression of acute kidney injury to chronic kidney disease.
Highlights
Despite recent advances in intensive care management, severe and dialysis-dependent acute kidney injury (AKI) occurs in more than 5% of critically ill patients and is associated with high mortality [1]
Values are shown as the mean ± S.E.M. *p < 0.05 vs. the sham group, †p < 0.05 vs. the contralateral kidney, #p < 0.05 vs. the ischemic/reperfusion injury (IRI) + saline group
Substance P (SP) is widely expressed in diverse cells, including epithelial cells, endothelial cells, immune cells, and mesenchymal stromal cells (MSCs) [20, 21]
Summary
Despite recent advances in intensive care management, severe and dialysis-dependent acute kidney injury (AKI) occurs in more than 5% of critically ill patients and is associated with high mortality [1]. Immune cell infiltration after injury and the subsequent development of inflammation are related to the critical progression of AKI to CKD [6, 7]. Because most of these experiments are performed using external MSCs, there are risks such as tumorigenicity and immunogenicity, which are well-known side effects of stem cell therapy [12]. Another issue of stem cell therapy is that some reports of improved immune-related cytokines have been published, few studies have examined how to modulate immune cell activation after AKI
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