Maladaptive Role of IL-6 in Ischemic Acute Renal Failure

Abstract

The role of IL-6 was investigated in murine ischemic acute renal failure. The renal pedicles were clamped for 17 min, and the mice were studied at various times after reperfusion. We found that serum IL-6 increased after murine ischemic renal injury. This increase was associated with increased IL-6 mRNA in the ischemic kidney but not in the contralateral kidney or the liver. Maximal IL-6 production occurred at 4 to 8 h and decreased to baseline by 24 h. Reperfusion of the kidney was required for IL-6 production. In situ hybridization and immunohistochemistry showed that macrophages infiltrated areas adjacent to the vascular bundles in the outer medulla within hours of reperfusion and showed that these macrophages produced IL-6 mRNA. For understanding how macrophages were stimulated to produce IL-6, an in vitro model in which S3 proximal tubular cells were injured by reactive oxygen species was set up. These injured cells released molecules that activated macrophages to produce IL-6 in vitro. IL-6 that was produced in response to renal ischemia was maladaptive because transgenic knockout of IL-6 ameliorated renal injury as measured by serum creatinine and histology. IL-6 transgenic knockout mice were lethally irradiated, and their bone marrow was reconstituted with wild-type IL-6 cells. Such bone marrow transfers abolished the protective effects of transgenic IL-6 knockout. It is concluded that macrophages infiltrate the area of the vascular bundles of the outer medulla, these macrophages produce IL-6, and this IL-6 exacerbates ischemic murine acute renal failure.

Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury*

“…Elevations in IL-6 are associated with acute kidney injury in animal models of ischemic acute tubular necrosis (30). In humans, Ahlstrom et al (31) reported that IL-6 levels differed among patients with systemic inflammatory response syndrome with and without acute kidney injury at days 2 and 3 of systemic inflammatory response syndrome.…”

Disruption of Guanylyl Cyclase-G Protects against Acute Renal Injury

“…34 Proinflammatory cytokine IL-6 was previously found to be produced by macrophages infiltrating adjacent to ischemic vascular bundles of the outer medulla. 22,23 A local increase in IL-6 was shown to promote PMN accumulation within the ischemic renal tissue by directly amplifying a substantial production of the proinflammatory cytokines IL-1␤ and TNF-␣ and/or an upregulation of the adhesion molecules intercellular adhesion molecule-1 and P-selectin on the endothelium. 22,23 Because we failed to localize GC-G expression in any of the infiltrating PMN or in the endothelial layer of peritubular capillaries and interlobular arteries (Figure 2, E and F), the effects of GC-G on I/R-induced inflammation might be mediated through an indirect mechanism in these cell types.…”

“…22,23 A local increase in IL-6 was shown to promote PMN accumulation within the ischemic renal tissue by directly amplifying a substantial production of the proinflammatory cytokines IL-1␤ and TNF-␣ and/or an upregulation of the adhesion molecules intercellular adhesion molecule-1 and P-selectin on the endothelium. 22,23 Because we failed to localize GC-G expression in any of the infiltrating PMN or in the endothelial layer of peritubular capillaries and interlobular arteries (Figure 2, E and F), the effects of GC-G on I/R-induced inflammation might be mediated through an indirect mechanism in these cell types. On the contrary, double immunostaining revealed that with I/R injury, GC-G and activated caspase-3 were co-localized to the same tubular cells (data not shown), which suggests that GC-Gmediated programmed cell death occurs primarily in renal tubular epithelial cells.…”

“…Because inhibition of apoptosis, IL-6, or P-selectin has been demonstrated to protect against I/R-induced organ failure in the kidney, 15,[22][23][24] heart, 35,36 brain, 37,38 intestine, 39 and liver, 40 GC-G may also be involved in I/R-induced abnormalities in other organs, such as acute myocardial infarction in the heart or stroke in the brain, which warrants further investigation. Although the exact mechanism by which GC-G is regulated under renal I/R remains undefined, a simple regulatory mechanism could be that renal I/R induces the release of endogenous ligand(s) and modulates GC-G activity to transmit the injury signal leading to apoptosis and inflammation.…”

“…19 -24 For example, expression of adhesion molecule P-selectin and proinflammatory cytokine IL-6 is induced in ischemic renal tissues, and its inhibition protects against I/R-induced renal failure in mice. [22][23][24] We thus compared the expression of P-selectin and IL-6 in kidneys of WT and GC-G Ϫ/Ϫ mice subjected to renal I/R. GC-G Ϫ/Ϫ mice showed marked reduction in P-selectin and IL-6 mRNA level as compared with WT controls ( Figure 6A).…”