Abstract
Podocyte injury is considered a major contributor to the development of diabetic nephropathy (DN). Therefore, identification of potential therapeutic targets for preventing podocyte injury has clinical importance. Recent studies have indicated that autophagy is a key homeostatic mechanism to maintaining podocyte integrity and function. This study was to elucidate the role of progranulin (PGRN), a secreted glycoprotein, in the modulation of podocyte autophagic process and podocyte injury under a diabetic condition. PGRN was downregulated in the kidney from diabetic mice and podocytes under a high-glucose (HG) condition. PGRN deficiency exacerbated the renal dysfunction and glomerular structural alterations. In vitro, treatment with recombinant human PGRN (rPGRN) attenuated HG-induced podocyte injury accompanied by enhanced autophagy. Inhibition of autophagy disturbed the protective effects of PGRN in HG-induced podocytotoxicity. Furthermore, PGRN induced autophagy via the PGRN-CAMKK-AMPK pathway. Collectively, our data identified the protective role of PGRN in podocyte injury via restoring autophagy and activating the CAMKK-AMPK pathway, which may pave the road to new therapeutic modalities for the treatment of diabetic nephropathy.
Key messages
• PGRN level is reduced in kidney of diabetic mice and high-glucose–treated podocytes.
• PGRN deficiency exacerbates renal injury in diabetic mice.
• PGRN protects against high-glucose–induced podocyte injury.
• PGRN restores high-glucose–inhibited autophagy in podocytes.
• CAMKK-AMPK pathway is required for the protective role of PGRN in podocyte injury.
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Funding
This study was supported by China National Funds for Distinguished Young Scientists to Yi F (81525005); the National Natural Science Foundation of China (91642204, 81470958, 81670629, 81600570, 81770726, 81873614, and 81700636); the Natural Science Foundation of Shandong Province (ZR2016HM03, ZR2017BH028); the Key R&D project of Shandong Province (2018GSF118027, 2017GSF218018).
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All animal studies were approved by the Institutional Animal Care and Use Committee of Shandong University (Document No. LL-201501025) and conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
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Zhou, D., Zhou, M., Wang, Z. et al. Progranulin alleviates podocyte injury via regulating CAMKK/AMPK-mediated autophagy under diabetic conditions. J Mol Med 97, 1507–1520 (2019). https://doi.org/10.1007/s00109-019-01828-3
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DOI: https://doi.org/10.1007/s00109-019-01828-3