Fetuin A exacerbates palmitic acid induced podocyte death and can be attenuated by antagonizing Il-1β

Abstract

Diabetic nephropathy (DN) has become a leading cause of end stage renal disease (ESRD) in industrialized countries, and most affected patients have type 2 diabetes (T2D). Over the last years it has become evident that sterile inflammation plays a central role in the pathogenesis of DN. Accumulation of macrophages was demonstrated in humans and rodent models of DN, and inhibition of inflammatory cell recruitment into the kidney was shown to be protective in experimental DN. In addition to immune cells, intrinsic renal cells, such as podocytes and mesangial cells, can also secrete pro-inflammatory cytokines, which may contribute to the inflammatory processand aggravate DN. The aim of the present study was to investigate whether palmitic acid, Fetuin-A or their combination elicit an inflammatory response involving toll- like receptor 4 (TLR4) in podocytes and whether this inflammatory pathway affects podocyte survival. Further, I aimed to investigate whether interleukin- 1β (IL-1β) signaling can modulate podocyte death. Finally, I performed a pilot study in diabetic mice to investigate whether inhibition of IL-1β with a murinized anti-IL-1β antibody may attenuate albuminuria and/or surrogate markers of DN. The present study uncovered that Fetuin-A or LPS exacerbate palmitic acid induced podocyte death, which is associated with a strong inflammatory response as indicated by the induction of monocyte chemoattractant protein- 1 (MCP-1) and keratinocyte chemoattractant (KC). Moreover, blockage of TLR4 dramatically decreased MCP-1 and KC secretion and attenuated podocyte death induced by palmitic acid alone and/or Fetuin-A in combination with palmitic acid. In addition, inhibition of IL-1 signaling by anakinra, a recombinant human IL-1Ra, or a murinized anti-IL-1β antibody attenuated the inflammatory response elicited by Fetuin-A and palmitic acid and -similar to TLR4-inhibition- attenuated podocyte death.In vivo, therapy of diabetic DBA/2J mice with an anti-IL-1β antibodyprevented an increase in serum Fetuin-A concentrations and considerablydecreased tumor necrosis factor alpha (TNF-alpha) secretion in the urine, which is thought to correlate reciprocally with DN progression. In the short term, however, therapy with the anti-IL-1β antibody was not able to protect from albuminuria. In summary, the results suggest that Fetuin-A leads to an inflammatory response in podocytes which exacerbates palmitic acid induced podocyte death. The data suggest also that TLR4 signaling plays a role as a modulator in the initiation and perturbation of the inflammatory process and leads to an exacerbation of palmitic acid induced podocyte death. In addition, this study implies a critical role for IL-1β signaling in palmitic acid induced podocyte death. In vivo, therapy of diabetic mice with an anti-IL-1β antibody favorably affected Fetuin-A levels in serum and urinary TNFα-levels, but in the short term a beneficial effect on albuminuria was absent, which gives the rational for prolonged studies to further test this new therapeutic approach.