Sterile inflammation is considered critical in the pathogenesis of diabetic nephropathy (DN). Here we show that Fetuin-A (FetA) or lipopolysaccharide (LPS) exacerbate palmitic acid-induced podocyte death, which is associated with a strong induction of monocyte chemoattractant protein-1 (MCP-1) and keratinocyte chemoattractant (KC). Moreover, blockage of TLR4 prevents MCP-1 and KC secretion and attenuates podocyte death induced by palmitic acid alone or combined with FetA. In addition, inhibition of interleukin-1 (IL-1) signaling by anakinra, a recombinant human IL-1Ra, or a murinized anti-IL-1β antibody attenuates the inflammatory and ultimate cell death response elicited by FetA alone or combined with palmitic acid. In vivo short-term therapy of diabetic DBA/2J mice with an anti-IL1-β antibody for 4 weeks prevented an increase in serum FetA and considerably decreased urinary tumor necrosis alpha (TNF-α), a known risk factor for DN progression. In summary, our results suggest that FetA similarly to LPS leads to an inflammatory response in podocytes, which exacerbates palmitic acid-induced podocyte death and our data imply a critical role for IL-1β signaling in this process. The study offers the rational for prolonged in vivo studies aimed at testing anti-IL-1β therapy for prevention and treatment of DN.,© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.