Fat is now recognized as a source of immunologically significant cytokines. Adiponectin, the most abundant adipokine, is usually classified as an anti-inflammatory cytokine because decreased adiponectin levels are associated clinically with cardiovascular disease and type 2 diabetes. In vitro, adiponectin decreases the production of TNFα, IL-6 and IFNγ by leukocytes, while increasing IL-10. In vivo, adiponectin knockout mice reject cardiac allografts more acutely. On the other hand, adiponectin deficiency is reported to protect the kidney from ischemia-reperfusion injury, and fibrosis. Although adipose tissue is the main source of adiponectin, other parenchymal tissues produce adiponectin, including both skeletal and cardiac muscle, vascular endothelial and smooth muscle cells. More recently, macrophages and lymphocytes have been found to produce adiponectin.

To determine the effects of adiponectin on immune responses to renal allografts, we transplanted A/J (H-2^a) kidneys to C57BL/6 (H-2^b) wild type or adiponectin knockout recipients. Animals were sacrificed at 6, 14, and 28 days. RNA was isolated from the kidneys and q-PCR was performed by the dd CT method. A panel of 39 genes were assessed including markers for inflammatory macrophages (M1) and wound healing macrophages (M2).

Renal allografts survived more than 28 days in both wild type and knockout mice. T cell and macrophage infiltrates progressively increased with time after transplantation. CXCL9 expression was increased 40-70 fold by day 6 and decreased to near control by day 28 in both groups. Other markers associated with M1 macrophages such as TNFα, IL-1β, CD80 and CD 86 followed a similar pattern but at lower levels (peak values 10-20 fold). In contrast, IL-10 progressively increased from 10-20 fold at day 6 to 20-80 fold at day 28 in both groups. Other M2 markers, such as Fizz1 and CD 206 followed a similar pattern at a lower level. Local expression of adiponectin was not detected in the renal allografts to either wild type or knockout recipients at 6 or 14 days even though the donors were wild type A/J mice. At 28 days adiponectin expression was increased (25-85 fold) in the allografts to the wild type but not the knockout recipients. Adiponectin expression was also increased in peripheral blood leukocytes as early as day 6.

Our data suggest that circulating wild type leukocytes express adiponectin and adiponectin expression increases in the allograft as the macrophages shift from a proinflammatory M1 to a wound healing M2 phenotype.

CITATION INFORMATION: Goparaju S, Fan R, Keslar K, Dvorina N, Baldwin III W. Adiponectin Is Produced by Leukocytes Infiltrating Renal Transplants. Am J Transplant. 2016;16 (suppl 3).

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