Immune mechanisms and novel pharmacological therapies of acute kidney injury

Abstract

Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and both innate and adaptive immunity contribute to the pathogenesis. Kidney resident cells promote inflammation after IRI by increasing endothelial cell adhesion molecule expression and vascular permeability. Kidney epithelial cells bind complement and express toll-like receptors and resident and infiltrating cells produce cytokines/chemokines. Early activation of kidney dendritic cells (DCs) initiates a cascade of events leading to accumulation of interferon-gamma-producing neutrophils, infiltrating macrophages, CD4(+) T cells, B cells and invariant natural killer T (NKT) cells. Recent studies from our laboratory now implicate the IL23/IL17 pathway in kidney IRI. Following the initial early phase of inflammation, the late phase involves infiltration of anti-inflammatory cells including regulatory T cells, alternatively activated macrophages and stem cells leading to attenuation of inflammation and initiation of repair. Based upon these immune mechanisms of injury, recent studies hold promise for novel drug therapies. These pharmacological agents have been shown to reduce inflammation or cytotoxicity in rodent models of AKI and some show early promise in clinical trials. This review summarizes recent advances to further our understanding of the immune mechanisms of AKI and potential pharmacological therapies.

Fig. (1)

Progenitor cells in tissue repair following AKI. A) Adjacent surviving epithelial cells dedifferentiate undergo epithelial-mesenchymal-epithelial (EME) transition into new epithelial cells, B) kidney specific adult stem cells may migrate to the site of injury or C) bone marrow derived mesenchymal or hematopoietic stem cells gain access to the injured epithelium and differentiate into mature epithelial cells.