Journal
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Volume 324, Issue 1, Pages 111-117Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.107.130161
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Funding
- NIDDK NIH HHS [K08-DK-65022, R01-DK-56851] Funding Source: Medline
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK056851, K08DK065022] Funding Source: NIH RePORTER
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Inflammatory mechanisms contribute to cisplatin-induced acute renal failure (CisARF). Our first aim was to determine renal macrophage infiltration in CisARF. A more than 2-fold increase in CD11b-positive macrophages in the kidney on day 2 preceded the increase in blood urea nitrogen (BUN) and serum creatinine (SCr). Our next aim was to determine the chemoattractant for macrophage infiltration in CisARF. Fractalkine (CX(3)CL1) is expressed on activated endothelial cells and is a potent chemoattractant for macrophages that express its receptor (CX(3)CR1). Immunoblotting showed that whole-kidney CX(3)CL1 expression on days 1, 2, and 3 after cisplatin administration was increased. On immunofluorescence, the intensity of renal endothelial staining of CX(3)CL1 in blood vessels was significantly increased on day 2. Circulating von Willebrand factor (vWF), a measure of systemic endothelial injury, was increased on day 2. Next we determined whether macrophages played an injurious role in CisARF. Macrophages were depleted with injections of liposome-encapsulated clodronate (LEC). LEC resulted in a decrease in renal CD11b-positive macrophages on day 3. However, LEC-treated mice were not protected from CisARF on day 3. To determine the role of CX(3)CR1, both a specific anti-CX(3)CR1 antibody and CX(3)CR1(-/-) mice were used. Administration of the CX(3)CR1 antibody and CX(3)CR1(-/-) mice was not protected against CisARF. In summary, in CisARF, macrophage infiltration in the kidney, CX(3)CL1 expression in whole kidney and blood vessels, and the increase in circulating vWF precede BUN and SCr increase. However, inhibition of macrophage infiltration in the kidney or CX(3)CR1 blockade is not sufficient to prevent CisARF.
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