Journal Article

Cytokine production increases and cytokine clearance decreases in mice with bilateral nephrectomy

Ana Andres-Hernando, Belda Dursun, Christopher Altmann, Nilesh Ahuja, Zhibin He, Rhea Bhargava, Charles E. Edelstein, Alkesh Jani, Thomas S. Hoke, Christina Klein and Sarah Faubel

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 27, issue 12, pages 4339-4347
Published in print December 2012 | ISSN: 0931-0509
Published online July 2012 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfs256
Cytokine production increases and cytokine clearance decreases in mice with bilateral nephrectomy

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Background

Serum cytokines are increased in patients with acute kidney injury (AKI) and predict increased mortality. It is widely assumed that increased renal production of cytokines is the source of increased serum cytokines; the role of extra-renal cytokine production and impaired renal cytokine clearance is less well studied. We hypothesized that cytokine production in AKI was mononuclear phagocyte dependent, independent of production by the kidneys, and that serum cytokine clearance would be impaired in AKI.

Methods

Bilateral nephrectomy was used as a model of AKI to assess cytokine production independent of kidney cytokine production. Mononuclear phagocytes were depleted utilizing intravenous (IV) administration of liposome-encapsulated clodronate (LEC). Twenty-three serum cytokines were determined utilizing a multiplex cytokine kit. Proteins for cytokines were determined in the spleen and liver by enzyme-linked immunosorbent assay. Recombinant cytokines were injected by IV into mice with bilateral nephrectomy to determine the effect of absent kidney function on serum cytokine clearance.

Results

Serum interleukin (IL)-6, chemokine (C-X-C motif) ligand 1 (CXCL1), IL-10, IL-1β, monocyte chemotactic protein 1 (MCP-1), IL-5 and eotaxin were increased in the serum of mice after bilateral nephrectomy and were reduced with LEC. Serum IL-12p40 and regulated upon activation, normal T-cell expressed, and secreted (RANTES) were increased after bilateral nephrectomy and were further increased with LEC. Spleen IL-6, CXCL1, IL-10 and IL-1β and liver IL-6 and IL-10 were increased after bilateral nephrectomy. After IV injection, IL-6, CXCL1, IL-10 and IL-1β had a prolonged serum cytokine appearance in mice with bilateral nephrectomy versus sham operation.

Conclusions

Increased mononuclear phagocyte production and impaired renal clearance contribute to serum cytokine accumulation in AKI, independent of kidney injury. The effect of AKI on cytokine production and clearance may contribute to the increased mortality of patients with AKI.

Keywords: chemokines; CXCL1; cytokines; IL-6; mononuclear phagocytes

Journal Article.  4701 words.  Illustrated.

Subjects: Nephrology

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