Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Haneda M, Utsunomiya K, Koya D, Babazono T, Moriya T, Makino H, Kimura K, Suzuki Y, Wada T, Ogawa S, Inaba M, Kanno Y, Shigematsu T, Masakane I, Tsuchiya K, Honda K, Ichikawa K, Shide K, Joint Committee on Diabetic N (2015) A new classification of diabetic nephropathy 2014: a report from Joint Committee on Diabetic Nephropathy. J Diabetes Investig 6:242–246

    PubMed  PubMed Central  Google Scholar 

  2. Hartleben B, Godel M, Meyer-Schwesinger C, Liu S, Ulrich T, Kobler S, Wiech T, Grahammer F, Arnold SJ, Lindenmeyer MT, Cohen CD, Pavenstadt H, Kerjaschki D, Mizushima N, Shaw AS, Walz G, Huber TB (2010) Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J Clin Invest 120:1084–1096

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y (2004) In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 15:1101–1111

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Sato S, Kitamura H, Adachi A, Sasaki Y, Ghazizadeh M (2006) Two types of autophagy in the podocytes in renal biopsy specimens: ultrastructural study. J Submicrosc Cytol Pathol 38:167–174

    CAS  PubMed  Google Scholar 

  5. Bechtel W, Helmstadter M, Balica J, Hartleben B, Kiefer B, Hrnjic F, Schell C, Kretz O, Liu S, Geist F, Kerjaschki D, Walz G, Huber TB (2013) Vps34 deficiency reveals the importance of endocytosis for podocyte homeostasis. J Am Soc Nephrol 24:727–743

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Fang L, Zhou Y, Cao H, Wen P, Jiang L, He W, Dai C, Yang J (2013) Autophagy attenuates diabetic glomerular damage through protection of hyperglycemia-induced podocyte injury. PLoS One 8:e60546

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Vallon V, Rose M, Gerasimova M, Satriano J, Platt KA, Koepsell H, Cunard R, Sharma K, Thomson SC, Rieg T (2013) Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am J Physiol Renal Physiol 304:F156–F167

    CAS  PubMed  Google Scholar 

  8. Kitada M, Takeda A, Nagai T, Ito H, Kanasaki K, Koya D (2011) Dietary restriction ameliorates diabetic nephropathy through anti-inflammatory effects and regulation of the autophagy via restoration of Sirt1 in diabetic Wistar fatty (fa/fa) rats: a model of type 2 diabetes. Exp Diabetes Res 2011:908185

    PubMed  PubMed Central  Google Scholar 

  9. Yang D, Livingston MJ, Liu Z, Dong G, Zhang M, Chen JK, Dong Z (2018) Autophagy in diabetic kidney disease: regulation, pathological role and therapeutic potential. Cell Mol Life Sci 75:669–688

    CAS  PubMed  Google Scholar 

  10. Kume S, Thomas MC, Koya D (2012) Nutrient sensing, autophagy, and diabetic nephropathy. Diabetes 61:23–29

    CAS  PubMed  Google Scholar 

  11. Ding Y, Choi ME (2015) Autophagy in diabetic nephropathy. J Endocrinol 224:R15–R30

    CAS  PubMed  Google Scholar 

  12. Tanaka Y, Kume S, Kitada M, Kanasaki K, Uzu T, Maegawa H, Koya D (2012) Autophagy as a therapeutic target in diabetic nephropathy. Exp Diabetes Res 2012:628978

    PubMed  Google Scholar 

  13. Kume S, Yamahara K, Yasuda M, Maegawa H, Koya D (2014) Autophagy: emerging therapeutic target for diabetic nephropathy. Semin Nephrol 34:9–16

    CAS  PubMed  Google Scholar 

  14. Chitramuthu BP, Bennett HPJ, Bateman A (2017) Progranulin: a new avenue towards the understanding and treatment of neurodegenerative disease. Brain 140:3081–3104

    PubMed  Google Scholar 

  15. Xu L, Zhou B, Li H, Liu J, Du J, Zang W, Wu S, Sun H (2015) Serum levels of progranulin are closely associated with microvascular complication in type 2 diabetes. Dis Markers 2015:357279

    PubMed  PubMed Central  Google Scholar 

  16. Richter J, Ebert T, Stolzenburg JU, Dietel A, Hopf L, Hindricks J, Kralisch S, Kratzsch J, Fasshauer M (2013) Response to comment on: Richter et al. Serum levels of the adipokine progranulin depend on renal function. Diabetes Care 36:410–414 Diabetes Care 36: e84

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Nicoletto BB, Krolikowski TC, Crispim D, Canani LH (2016) Serum and urinary progranulin in diabetic kidney disease. PLoS One 11:e0165177

    PubMed  PubMed Central  Google Scholar 

  18. Liu M, Liang K, Zhen J, Zhou M, Wang X, Wang Z, Wei X, Zhang Y, Sun Y, Zhou Z, Su H, Zhang C, Li N, Gao C, Peng J, Yi F (2017) Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling. Nat Commun 8:413

    PubMed  PubMed Central  Google Scholar 

  19. Coward RJ, Welsh GI, Yang J, Tasman C, Lennon R, Koziell A, Satchell S, Holman GD, Kerjaschki D, Tavare JM, Mathieson PW, Saleem MA (2005) The human glomerular podocyte is a novel target for insulin action. Diabetes 54:3095–3102

    CAS  PubMed  Google Scholar 

  20. Saleem MA, O'Hare MJ, Reiser J, Coward RJ, Inward CD, Farren T, Xing CY, Ni L, Mathieson PW, Mundel P (2002) A conditionally immortalized human podocyte cell line demonstrating nephrin and podocin expression. J Am Soc Nephrol 13:630–638

    CAS  PubMed  Google Scholar 

  21. Shankland SJ, Pippin JW, Reiser J, Mundel P (2007) Podocytes in culture: past, present, and future. Kidney Int 72:26–36

    CAS  PubMed  Google Scholar 

  22. Zhou M, Tang W, Fu Y, Xu X, Wang Z, Lu Y, Liu F, Yang X, Wei X, Zhang Y, Liu J, Geng X, Zhang C, Wan Q, Li N, Yi F (2015) Progranulin protects against renal ischemia/reperfusion injury in mice. Kidney Int 87:918–929

    CAS  PubMed  Google Scholar 

  23. Du P, Fan B, Han H, Zhen J, Shang J, Wang X, Li X, Shi W, Tang W, Bao C, Wang Z, Zhang Y, Zhang B, Wei X, Yi F (2013) NOD2 promotes renal injury by exacerbating inflammation and podocyte insulin resistance in diabetic nephropathy. Kidney Int 84:265–276

    CAS  PubMed  Google Scholar 

  24. Wang X, Liu J, Zhen J, Zhang C, Wan Q, Liu G, Wei X, Zhang Y, Wang Z, Han H, Xu H, Bao C, Song Z, Zhang X, Li N, Yi F (2014) Histone deacetylase 4 selectively contributes to podocyte injury in diabetic nephropathy. Kidney Int 86:712–725

    CAS  PubMed  Google Scholar 

  25. Kimura S, Noda T, Yoshimori T (2007) Dissection of the autophagosome maturation process by a novel reporter protein, tandem fluorescent-tagged LC3. Autophagy 3:452–460

    CAS  PubMed  Google Scholar 

  26. Tang W, Lu Y, Tian QY, Zhang Y, Guo FJ, Liu GY, Syed NM, Lai Y, Lin EA, Kong L, Su J, Yin F, Ding AH, Zanin-Zhorov A, Dustin ML, Tao J, Craft J, Yin Z, Feng JQ, Abramson SB, Yu XP, Liu CJ (2011) The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 332:478–484

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Pagtalunan ME, Miller PL, Jumping-Eagle S, Nelson RG, Myers BD, Rennke HG, Coplon NS, Sun L, Meyer TW (1997) Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest 99:342–348

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Li H, Zhou B, Xu L, Liu J, Zang W, Wu S, Sun H (2014) Circulating PGRN is significantly associated with systemic insulin sensitivity and autophagic activity in metabolic syndrome. Endocrinology 155:3493–3507

    PubMed  Google Scholar 

  29. Guo Q, Xu L, Li H, Sun H, Liu J, Wu S, Zhou B (2017) Progranulin causes adipose insulin resistance via increased autophagy resulting from activated oxidative stress and endoplasmic reticulum stress. Lipids Health Dis 16:25

    PubMed  PubMed Central  Google Scholar 

  30. Tian R, Li Y, Yao X (2016) PGRN suppresses inflammation and promotes autophagy in keratinocytes through the Wnt/beta-catenin signaling pathway. Inflammation 39:1387–1394

    CAS  PubMed  Google Scholar 

  31. Altmann C, Hardt S, Fischer C, Heidler J, Lim HY, Haussler A, Albuquerque B, Zimmer B, Moser C, Behrends C, Koentgen F, Wittig I, Schmidt MHH, Clement AM, Deller T, Tegeder I (2016) Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: role of autophagy. Neurobiol Dis 96:294–311

    CAS  PubMed  Google Scholar 

  32. Chang MC, Srinivasan K, Friedman BA, Suto E, Modrusan Z, Lee WP, Kaminker JS, Hansen DV, Sheng M (2017) Progranulin deficiency causes impairment of autophagy and TDP-43 accumulation. J Exp Med 214:2611–2628

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Liu J, Li H, Zhou B, Xu L, Kang X, Yang W, Wu S, Sun H (2015) PGRN induces impaired insulin sensitivity and defective autophagy in hepatic insulin resistance. Mol Endocrinol 29:528–541

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, Jimenez-Sanchez M, Korolchuk VI, Lichtenberg M, Luo S, Massey DC, Menzies FM, Moreau K, Narayanan U, Renna M, Siddiqi FH, Underwood BR, Winslow AR, Rubinsztein DC (2010) Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 90:1383–1435

    CAS  PubMed  Google Scholar 

  35. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, Asara JM, Fitzpatrick J, Dillin A, Viollet B, Kundu M, Hansen M, Shaw RJ (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331:456–461

    CAS  PubMed  Google Scholar 

  36. Lee JW, Park S, Takahashi Y, Wang HG (2010) The association of AMPK with ULK1 regulates autophagy. PLoS One 5:e15394

    PubMed  PubMed Central  Google Scholar 

  37. Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13:132–141

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Kim J, Kim YC, Fang C, Russell RC, Kim JH, Fan W, Liu R, Zhong Q, Guan KL (2013) Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell 152:290–303

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Lieberthal W, Levine JS (2009) The role of the mammalian target of rapamycin (mTOR) in renal disease. J Am Soc Nephrol 20:2493–2502

    CAS  PubMed  Google Scholar 

  40. Mori H, Inoki K, Masutani K, Wakabayashi Y, Komai K, Nakagawa R, Guan KL, Yoshimura A (2009) The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential. Biochem Biophys Res Commun 384:471–475

    CAS  PubMed  Google Scholar 

  41. Godel M, Hartleben B, Herbach N, Liu S, Zschiedrich S, Lu S, Debreczeni-Mor A, Lindenmeyer MT, Rastaldi MP, Hartleben G, Wiech T, Fornoni A, Nelson RG, Kretzler M, Wanke R, Pavenstadt H, Kerjaschki D, Cohen CD, Hall MN, Ruegg MA, Inoki K, Walz G, Huber TB (2011) Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest 121:2197–2209

    PubMed  PubMed Central  Google Scholar 

  42. Lee MJ, Feliers D, Mariappan MM, Sataranatarajan K, Mahimainathan L, Musi N, Foretz M, Viollet B, Weinberg JM, Choudhury GG, Kasinath BS (2007) A role for AMP-activated protein kinase in diabetes-induced renal hypertrophy. Am J Physiol Renal Physiol 292:F617–F627

    CAS  PubMed  Google Scholar 

  43. Ding DF, You N, Wu XM, Xu JR, Hu AP, Ye XL, Zhu Q, Jiang XQ, Miao H, Liu C, Lu YB (2010) Resveratrol attenuates renal hypertrophy in early-stage diabetes by activating AMPK. Am J Nephrol 31:363–374

    CAS  PubMed  Google Scholar 

  44. Kitada M, Kume S, Imaizumi N, Koya D (2011) Resveratrol improves oxidative stress and protects against diabetic nephropathy through normalization of Mn-SOD dysfunction in AMPK/SIRT1-independent pathway. Diabetes 60:634–643

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Alers S, Loffler AS, Wesselborg S, Stork B (2012) Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol 32:2–11

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Luo Z, Zang M, Guo W (2010) AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future Oncol 6:457–470

    CAS  PubMed  Google Scholar 

  47. Bhandari V, Daniel R, Lim PS, Bateman A (1996) Structural and functional analysis of a promoter of the human granulin/epithelin gene. Biochem J 319(Pt 2):441–447

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Frampton G, Invernizzi P, Bernuzzi F, Pae HY, Quinn M, Horvat D, Galindo C, Huang L, McMillin M, Cooper B, Rimassa L, DeMorrow S (2012) Interleukin-6-driven progranulin expression increases cholangiocarcinoma growth by an Akt-dependent mechanism. Gut 61:268–277

    CAS  PubMed  Google Scholar 

Download references

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).

Author information

Author notes

  1. Di Zhou and Meng Zhou contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, School of Basic Medical Sciences, Shandong University, 44#, Wenhua Xi Road, Jinan, Shandong, 250012, People’s Republic of China

    Di Zhou, Meng Zhou, Ziying Wang, Yi Fu, Meng Jia, Xiaojie Wang, Min Liu, Yan Zhang, Yu Sun & Fan Yi

  2. Department of Pharmacy, The Second Hospital of Shandong University, Jinan, 250033, People’s Republic of China

    Meng Zhou

  3. Department of Pathogenic Biology, School of Basic Medical Sciences, Shandong University, 44#, Wenhua Xi Road, Jinan, Shandong, 250012, People’s Republic of China

    Yabin Zhou & Wei Tang

  4. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, People’s Republic of China

    Yi Lu

  5. Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Sciences, Shandong University, Jinan, 250012, People’s Republic of China

    Wei Tang & Fan Yi

  6. State Key Laboratory of Microbial Technology, Shandong University, Jinan, 250100, People’s Republic of China

    Fan Yi

Authors
  1. Di Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meng Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ziying Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Meng Jia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaojie Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Min Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yu Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yabin Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yi Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Wei Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Fan Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Wei Tang or Fan Yi.

Ethics declarations

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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 3116 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-019-01828-3

Keywords

Search

Navigation