Leptin, one of the typical
adipokines, is reported to promote Th17 cell responses and to enhance production of proinflammatory
cytokines. To clarify the role of
leptin in the regulation of the IL-23/IL-17 axis and the development of
kidney disease, we used a murine model of nephrotoxic serum (NTS)
nephritis (NTN). Sheep NTS was administered in wild-type C57BL/6J mice and food-restricted,
leptin-deficient C57BL/6J-ob/ob(FR-ob/ob) mice after preimmunization with sheep
IgG. The profile of
mRNA expression relevant to T helper lymphocytes in the kidneys was analyzed by quantitative real-time PCR (qRT-PCR). Cultured murine glomerular podocytes and peritoneal exudate macrophages (
PEMs) were used to investigate the direct effect of
leptin on
IL-23 or MCP-1 production by qRT-PCR. Kidney injury and macrophage infiltration were significantly attenuated in FR-ob/obmice 7 days after NTS injection. The Th17-dependent secondary immune response against deposited NTS in the glomeruli was totally impaired in FR-ob/obmice because of deteriorated
IL-17 and proinflammatory
cytokine production including
IL-23 and MCP-1 in the kidney.
IL-23 was produced in glomerular podocytes in NTN mice and cultured murine glomerular podocytes produced
IL-23 under
leptin stimulation. MCP-1 production in
PEMs was also promoted by
leptin. Induction of MCP-1 expression was observed in
PEMs regardless of Ob-Rb, and the
leptin signal was transduced without STAT3 phosphorylation in
PEMs.
Leptin deficiency impairs the secondary immune response against NTS and down-regulates
IL-23 production and Th17 responses in the NTN kidney, which is accompanied by decreased MCP-1 production and macrophage infiltration in the NTN kidney.