Macrophage Dynamics in AKI to CKD Progression

Abstract

Stemming from the recent and robust clinical data confirming that AKI does indeed increase the likelihood of developing CKD (reviewed by Chawla and Kimmel 1 ), numerous preclinical studies have offered insight into how the transition from AKI to CKD occurs. However, our understanding of this multifactorial process is incomplete. This knowledge is critical if we are to advance therapeutic strategies to combat the detrimental progression of renal injury. The development of CKD is thought to be promoted by an aberrant wound healing response involving tubular epithelial cells (TECs), fibroblasts, pericytes, myofibroblasts, fibrocytes, immune cells, and others, which leads to progressive fibrosis in the kidney and loss of viable nephrons. 2 Previous studies have demonstrated that cell cycle arrest of TECs, 3 as well as epigenetic modifications in renal fibroblasts, 4 are key components in fibrogenesis and the decline in renal function. In an integrated model, 5 cell cycle arrest of TECs leads to unchecked production of profibrotic mediators such as TGF-b and connective tissue growth factor, which induce sustained fibroblast activation and proliferation causing excessive extracellular matrix production, establishment of fibrotic lesions, and CKD. The inflammatory nature of AKI, involving resident cells of the renal mononuclear phagocytic system 6,7 and infiltrating immune cells, 8 suggests that leukocytes and their products would also influence the fate of the injured kidney. For example, sustained leukocyte accumulation and activation inside the kidney would promote extended periods of ischemia due to vascular congestion and may induce direct tubular and endothelial cell damage by the release of inflammatory mediators. Macrophages are among the innate leukocytes that rapidly accumulate in the kidney and promote inflammation in the acute phase of AKI, 9,10 yet macrophages also have a critical role in wound healing as scavengers of proinflammatory cell debris and as promoters of regeneration. 7,10-13 It should be mentioned here that the study of renal resident and/or infiltrating monocytes, macrophages, and dendritic cells is complicated by the overlapping phenotypes and surface marker expression by these different cell types in the kidney during health and injury, 7 and use of the term macrophage to describe the cell types discussed herein is for simplicity.The dual role of macrophages in AKI and subsequent repair and regeneration can be explained by the multiple phenotypes that a macrophage can adopt. There are several different major classifications of macrophage phenotype, including M1 (classically activated) and M2 (alternatively activated) macrophages. Most macrophages fall somewhere in the spectrum between M1 and M2 and may change their characteristics depending on their environment. 13 M1 macrophages are considered proinflammatory and make cytokines such as IL-1, IL-6, and TNF-a, whereas M2 are mainly anti-inflammatory and express arginase, mannose receptor, IL-10, and IL-4 receptor-a. 13 Thus, macrophages disp...

Protective effect of lyophilized recombinant human brain natriuretic peptide on renal ischemia/reperfusion injury in mice

“…It has been previously shown that BNP can inhibit cardiac inflammation induced by IRI (Hu et al, 2014). We also observed macrophage infiltration at an early stage of IRI (24 h after reperfusion) and noticed a pro-inflammatory phenotype of the macrophages (Kinsey, 2014;Huen and Cantley, 2015). However, the number of macrophages declined after BNP intervention.…”

The administration of erythropoietin attenuates kidney injury induced by ischemia/reperfusion with increased activation of Wnt/β-catenin signaling

“…During the early stages of IRI, macrophages have a proinflammatory role in mediating injury; during the late phase, they transform themselves into the anti-inflammatory phenotype to repair injury. 37,38 In this study, the increase in CD68þ macrophages could be mitigated by EPO treatment after IRI.…”

Targeting Endogenous Repair Pathways after AKI

“…For example, macrophages deliver reparative Wnt7b to tubular epithelia, enhancing proliferation and restoration of a functioning nephron. 58,59 A summary of the most recent findings for other therapeutic targets is presented in Tables 1 and 2.…”