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Journal of Molecular Medicine

, Volume 97, Issue 11, pp 1507–1520 | Cite as

Progranulin alleviates podocyte injury via regulating CAMKK/AMPK-mediated autophagy under diabetic conditions

  • Di Zhou
  • Meng Zhou
  • Ziying Wang
  • Yi Fu
  • Meng Jia
  • Xiaojie Wang
  • Min Liu
  • Yan Zhang
  • Yu Sun
  • Yabin Zhou
  • Yi Lu
  • Wei TangEmail author
  • Fan YiEmail author
Original Article

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.

Keywords

Diabetic nephropathy PGRN Autophagy CAMKK-AMPK pathway Podocyte 

Notes

Funding information

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).

Compliance with ethical standards

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.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

109_2019_1828_MOESM1_ESM.pdf (3 mb)
ESM 1 (PDF 3116 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology, School of Basic Medical SciencesShandong UniversityJinanPeople’s Republic of China
  2. 2.Department of PharmacyThe Second Hospital of Shandong UniversityJinanPeople’s Republic of China
  3. 3.Department of Pathogenic Biology, School of Basic Medical SciencesShandong UniversityJinanPeople’s Republic of China
  4. 4.Department of Biochemistry and Molecular Biology, School of Basic Medical SciencesShandong UniversityJinanPeople’s Republic of China
  5. 5.Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical SciencesShandong UniversityJinanPeople’s Republic of China
  6. 6.State Key Laboratory of Microbial TechnologyShandong UniversityJinanPeople’s Republic of China

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