BACKGROUND: Interleukin-6 (IL6) is an important regulator of cellular hypertrophy through the gp130/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway. We tested the hypothesis that IL6 and its downstream gp130/JAK2/STAT3 pathway participated in high glucose (HG)–induced podocyte hypertrophy. METHODS: IL6 levels in the media and lysates of podocytes were measured by enzyme-linked immunosorbent assay. Western blots were performed to determine the protein expression levels of gp130/JAK2/STAT3 among podocytes cultured with normal glucose (NG), NG + mannitol, NG + recombinant IL6, HG, and HG + IL6-neutralizing antibodies (IL6NAb). Immunoprecipitation was examined to determine whether gp130 interacted with JAK2 in response to HG or IL6. Podocyte hypertrophy was verified using protein/cell counts and flow cytometry. RESULTS: IL6 levels were significantly increased in the media and lysates of podocytes cultured in HG compared with the NG groups. The nuclear phospho-STAT3/STAT3 ratio was increased by HG and NG + IL6 and was attenuated in the HG + IL6NAb groups, indicating that nuclear STAT3 was activated following JAK2 and cytosolic STAT3 activation in response to IL6 secreted by HG-stimulated podocytes. Immunoprecipitation showed increased phospho-JAK2 recruitment to gp130 in the HG and NG + IL6 groups, and the addition of IL6NAb in the HG group significantly abrogated these increases. Podocyte hypertrophy was significantly increased in the HG and NG + IL6 compared with the NG condition and was diminished by the addition of IL6NAbs to the HG group. CONCLUSION: IL6 might play a prominent role in the local activation of JAK2/STAT3 in podocyte hypertrophy under HG conditions. In vivo studies examining this pathway are warranted.