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bioRxiv · 10.1101/2020.12.28.424520

Increased ketohexokinase-A governs fructose-induced podocyte hypertrophy by IL-6/STAT3 signaling activation

Zhou, J.·Zhang, D.-M.·Yang, J.·Ding, H.·Li, T.-S.·Liu, Z.-H.·Chen, L.·Jiao, R.-Q.·Kong, L.-D.
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Abstract

Glomerular hypertrophy is crucial for podocyte damage and proteinuria. Our previous study showed that fructose induced podocyte injury. However, the molecular mechanism underlying podocyte hypertrophy under fructose is unclear. We observed that fructose significantly initiated the hypertrophy in rat glomeruli and cultured differentiated human podocytes (HPCs). Consistently, it induced inflammatory response with the down-regulation of zinc-finger protein tristetraprolin (TTP) and the activation of interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling in these animal and cell models. Subsequently, high-expression of miR-92a-3p and its target protein cyclin-dependent kinase inhibitor p57 (P57) down-regulation, representing the abnormal proliferation and apoptosis, were observed in vivo and in vitro. Moreover, fructose increased ketohexokinase-A (KHK-A) in rat glomeruli and HPCs. Animal-free recombinant human IL-6, maslinic acid and TTP siRNA were used to manifest that fructose may decrease TTP to activate IL-6/STAT3 signaling in podocyte overproliferation and apoptosis, causing podocyte hypertrophy. KHK-A siRNA transfection further demonstrated that the inactivation of IL-6/STAT3 to relieve podocyte hypertrophy mediated by inhibiting KHK-A to increase TTP may be a novel strategy for fructose-associated podocyte injury and proteinuria. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/424520v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@243c32org.highwire.dtl.DTLVardef@ec1784org.highwire.dtl.DTLVardef@1fbe0b6org.highwire.dtl.DTLVardef@15dd5f3_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Zhou, J., Zhang, D.-M., Yang, J., Ding, H., Li, T.-S., Liu, Z.-H., Chen, L., Jiao, R.-Q., Kong, L.-D.. 2020-12-29. Increased ketohexokinase-A governs fructose-induced podocyte hypertrophy by IL-6/STAT3 signaling activation. https://doi.org/10.1101/2020.12.28.424520

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