Mediators of inflammation in acute kidney injury

Abstract

Acute kidney injury (AKI) remains to be an independent risk factor for mortality and morbidity. Inflammation is now believed to play a major role in the pathophysiology of AKI. It is hypothesized that in ischemia, sepsis and nephrotoxic models that the initial insult results in morphological and/or functional changes in vascular endothelial cells and/or in tubular epithelium. Then, leukocytes including neutrophils, macrophages, natural killer cells, and lymphocytes infiltrate into the injured kidneys. The injury induces the generation of inflammatory mediators like cytokines and chemokines by tubular and endothelial cells which contribute to the recruiting of leukocytes into the kidneys. Thus, inflammation has an important role in the initiation and extension phases of AKI. This review will focus on the mediators of inflammation contributing to the pathogenesis of AKI.

Figure 1

Inflammatory pathogenesis of AKI. AKI results in the upregulation of chemokines like fractalkine and CXCL1 and adhesion molecules like P-selectin in the endothelium of blood vessels in the kidney. Upregulation of chemokines and adhesion molecules in the endothelium results in the infiltration of inflammatory cells like neutrophils (N), lymphocytes (L), and macrophages (M) from the blood vessels into the interstitium of the kidney. Proximal tubular epithelial cells produce cytokines like IL-18 and IL-6. IL-18 and IL-6 produced by the proximal tubule enter the interstitium and result in activation and/or proliferation of neutrophils (N), lymphocytes (L), and macrophages (M). IL-18 and IL-6 are also released from the proximal tubular cells into the tubular lumen where they serve as early urinary diagnostic biomarkers of AKI. Inflammatory cells produce vasoconstrictors (prostaglandins, leukotrienes, and thromboxanes) that may affect vascular injury and oxygen radicals that may worsen tubular and vascular injury. Resident dendritic cells (DCs) form a contiguous network throughout the entire kidney. The role of DCs in AKI is not well understood. Following kidney ischemia-perfusion, resident dentritic cells release cytokines like TNF and IL-6 and chemokines like MCP-1.