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CCDC92 promotes podocyte injury by regulating PA28α/ABCA1/cholesterol efflux axis in type 2 diabetic mice

Acta Pharmacologica Sinica volume 45, pages 1019–1031 (2024)Cite this article

Abstract

Podocyte lipotoxicity mediated by impaired cellular cholesterol efflux plays a crucial role in the development of diabetic kidney disease (DKD), and the identification of potential therapeutic targets that regulate podocyte cholesterol homeostasis has clinical significance. Coiled-coil domain containing 92 (CCDC92) is a novel molecule related to metabolic disorders and insulin resistance. However, whether the expression level of CCDC92 is changed in kidney parenchymal cells and the role of CCDC92 in podocytes remain unclear. In this study, we found that Ccdc92 was significantly induced in glomeruli from type 2 diabetic mice, especially in podocytes. Importantly, upregulation of Ccdc92 in glomeruli was positively correlated with an increased urine albumin-to-creatinine ratio (UACR) and podocyte loss. Functionally, podocyte-specific deletion of Ccdc92 attenuated proteinuria, glomerular expansion and podocyte injury in mice with DKD. We further demonstrated that Ccdc92 contributed to lipid accumulation by inhibiting cholesterol efflux, finally promoting podocyte injury. Mechanistically, Ccdc92 promoted the degradation of ABCA1 by regulating PA28α-mediated proteasome activity and then reduced cholesterol efflux. Thus, our studies indicate that Ccdc92 contributes to podocyte injury by regulating the PA28α/ABCA1/cholesterol efflux axis in DKD.

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Fig. 1: Ccdc92 was involved in podocyte injury under diabetic kidney disease.
Fig. 2: Ccdc92 deficiency attenuated podocyte injury in DKD.
Fig. 3: Ccdc92 contributed to podocyte lipotoxicity under diabetic conditions.
Fig. 4: Ccdc92 contributed to podocyte lipotoxicity by inhibiting ABCA1-mediated cholesterol efflux.
Fig. 5: Ccdc92 deficiency increased the protein level of ABCA1 through the proteasome pathway.
Fig. 6: Ccdc92 promoted HG-induced proteasome activity in podocytes by binding to PA28α.
Fig. 7: The Ccdc92 ∆aa59–113 mutation counteracted the effects of Ccdc92 on podocyte lipotoxicity.

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Data availability

The proteomics data presented in this study are openly available in ProteomeXchange with identifier PXD036050. Other data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. John S. Complication in diabetic nephropathy. Diabetes Metab Syndr. 2016;10:247–9.

    Article  PubMed  Google Scholar 

  2. Fu Y, Sun Y, Wang M, Hou Y, Huang W, Zhou D, et al. Elevation of JAML promotes diabetic kidney disease by modulating podocyte lipid metabolism. Cell Metab. 2020;32:1052–62.e8.

    Article  CAS  PubMed  Google Scholar 

  3. DeFronzo RA, Reeves WB, Awad AS. Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors. Nat Rev Nephrol. 2021;17:319–34.

    Article  CAS  PubMed  Google Scholar 

  4. Wahl P, Ducasa GM, Fornoni A. Systemic and renal lipids in kidney disease development and progression. Am J Physiol Ren Physiol. 2016;310:F433–45.

    Article  CAS  Google Scholar 

  5. Brinkkoetter PT, Bork T, Salou S, Liang W, Mizi A, Ozel C, et al. Anaerobic glycolysis maintains the glomerular filtration barrier independent of mitochondrial metabolism and dynamics. Cell Rep. 2019;27:1551–66.e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pedigo CE, Ducasa GM, Leclercq F, Sloan A, Mitrofanova A, Hashmi T, et al. Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury. J Clin Invest. 2016;126:3336–50.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Herman-Edelstein M, Scherzer P, Tobar A, Levi M, Gafter U. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J Lipid Res. 2014;55:561–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ducasa GM, Mitrofanova A, Mallela SK, Liu X, Molina J, Sloan A, et al. ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes. J Clin Invest. 2019;129:3387–400.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Huang LO, Rauch A, Mazzaferro E, Preuss M, Carobbio S, Bayrak CS, et al. Genome-wide discovery of genetic loci that uncouple excess adiposity from its comorbidities. Nat Metab. 2021;3:228–43.

    Article  CAS  PubMed  Google Scholar 

  10. Vujkovic M, Keaton JM, Lynch JA, Miller DR, Zhou J, Tcheandjieu C, et al. Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis. Nat Genet. 2020;52:680–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhao W, Rasheed A, Tikkanen E, Lee JJ, Butterworth AS, Howson JMM, et al. Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease. Nat Genet. 2017;49:1450–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Klarin D, Zhu QM, Emdin CA, Chaffin M, Horner S, McMillan BJ, et al. Genetic analysis in UK Biobank links insulin resistance and transendothelial migration pathways to coronary artery disease. Nat Genet. 2017;49:1392–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ren L, Du W, Song D, Lu H, Hamblin MH, Wang C, et al. Genetic ablation of diabetes-associated gene Ccdc92 reduces obesity and insulin resistance in mice. iScience. 2023;26:105769.

    Article  CAS  PubMed  Google Scholar 

  14. Wang Z, Jiang T, Li J, Proctor G, McManaman JL, Lucia S, et al. Regulation of renal lipid metabolism, lipid accumulation, and glomerulosclerosis in FVBdb/db mice with type 2 diabetes. Diabetes. 2005;54:2328–35.

    Article  CAS  PubMed  Google Scholar 

  15. Fornoni A, Merscher S, Kopp JB. Lipid biology of the podocyte—new perspectives offer new opportunities. Nat Rev Nephrol. 2014;10:379–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nijholt DA, de Graaf TR, van Haastert ES, Oliveira AO, Berkers CR, Zwart R, et al. Endoplasmic reticulum stress activates autophagy but not the proteasome in neuronal cells: implications for Alzheimer’s disease. Cell Death Differ. 2011;18:1071–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lee DH, Goldberg AL. Proteasome inhibitors: valuable new tools for cell biologists. Trends Cell Biol. 1998;8:397–403.

    Article  CAS  PubMed  Google Scholar 

  18. Collins GA, Goldberg AL. The logic of the 26 S proteasome. Cell. 2017;169:792–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lesne J, Locard-Paulet M, Parra J, Zivkovic D, Menneteau T, Bousquet MP, et al. Conformational maps of human 20 S proteasomes reveal PA28- and immuno-dependent inter-ring crosstalks. Nat Commun. 2020;11:6140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Vartak T, Godson C, Brennan E. Therapeutic potential of pro-resolving mediators in diabetic kidney disease. Adv Drug Deliv Rev. 2021;178:113965.

    Article  CAS  PubMed  Google Scholar 

  21. Kim Y, Lim JH, Kim MY, Kim EN, Yoon HE, Shin SJ, et al. The adiponectin receptor agonist adiporon ameliorates diabetic nephropathy in a model of type 2 diabetes. J Am Soc Nephrol. 2018;29:1108–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Patel M, Wang XX, Magomedova L, John R, Rasheed A, Santamaria H, et al. Liver X receptors preserve renal glomerular integrity under normoglycaemia and in diabetes in mice. Diabetologia. 2014;57:435–46.

    Article  CAS  PubMed  Google Scholar 

  23. Kang HM, Ahn SH, Choi P, Ko YA, Han SH, Chinga F, et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat Med. 2015;21:37–46.

    Article  CAS  PubMed  Google Scholar 

  24. Schelling JR. The contribution of lipotoxicity to diabetic kidney disease. Cells. 2022;11:3236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Song Y, Liu J, Zhao K, Gao L, Zhao J. Cholesterol-induced toxicity: An integrated view of the role of cholesterol in multiple diseases. Cell Metab. 2021;33:1911–25.

    Article  CAS  PubMed  Google Scholar 

  26. Merscher-Gomez S, Guzman J, Pedigo CE, Lehto M, Aguillon-Prada R, Mendez A, et al. Cyclodextrin protects podocytes in diabetic kidney disease. Diabetes. 2013;62:3817–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yang Q, Hu J, Yang Y, Chen Z, Feng J, Zhu Z, et al. Sirt6 deficiency aggravates angiotensin II-induced cholesterol accumulation and injury in podocytes. Theranostics. 2020;10:7465–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang N, Silver DL, Thiele C, Tall AR. ATP-binding cassette transporter A1 (ABCA1) functions as a cholesterol efflux regulatory protein. J Biol Chem. 2001;276:23742–7.

    Article  CAS  PubMed  Google Scholar 

  29. Oram JF, Lawn RM. ABCA1. The gatekeeper for eliminating excess tissue cholesterol. J Lipid Res. 2001;42:1173–9.

    Article  CAS  PubMed  Google Scholar 

  30. Pohl C, Dikic I. Cellular quality control by the ubiquitin-proteasome system and autophagy. Science. 2019;366:818–22.

    Article  CAS  PubMed  Google Scholar 

  31. Meyer-Schwesinger C. The ubiquitin-proteasome system in kidney physiology and disease. Nat Rev Nephrol. 2019;15:393–411.

    Article  PubMed  Google Scholar 

  32. Beeken M, Lindenmeyer MT, Blattner SM, Radon V, Oh J, Meyer TN, et al. Alterations in the ubiquitin proteasome system in persistent but not reversible proteinuric diseases. J Am Soc Nephrol. 2014;25:2511–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Goru SK, Kadakol A, Gaikwad AB. Hidden targets of ubiquitin proteasome system: to prevent diabetic nephropathy. Pharmacol Res. 2017;120:170–9.

    Article  CAS  PubMed  Google Scholar 

  34. Sharpe LJ, Cook EC, Zelcer N, Brown AJ. The UPS and downs of cholesterol homeostasis. Trends Biochem Sci. 2014;39:527–35.

    Article  CAS  PubMed  Google Scholar 

  35. Ogura M, Ayaori M, Terao Y, Hisada T, Iizuka M, Takiguchi S, et al. Proteasomal inhibition promotes ATP-binding cassette transporter A1 (ABCA1) and ABCG1 expression and cholesterol efflux from macrophages in vitro and in vivo. Arterioscler Thromb Vasc Biol. 2011;31:1980–7.

    Article  CAS  PubMed  Google Scholar 

  36. Chaki M, Airik R, Ghosh AK, Giles RH, Chen R, Slaats GG, et al. Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell. 2012;150:533–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bernatik O, Pejskova P, Vyslouzil D, Hanakova K, Zdrahal Z, Cajanek L. Phosphorylation of multiple proteins involved in ciliogenesis by Tau Tubulin kinase 2. Mol Biol Cell. 2020;31:1032–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yadranji Aghdam S, Mahmoudpour A. Proteasome activators, PA28alpha and PA28beta, govern development of microvascular injury in diabetic nephropathy and retinopathy. Int J Nephrol. 2016;2016:3846573.

    Article  PubMed  PubMed Central  Google Scholar 

  39. de Haan W, Bhattacharjee A, Ruddle P, Kang MH, Hayden MR. ABCA1 in adipocytes regulates adipose tissue lipid content, glucose tolerance, and insulin sensitivity. J Lipid Res. 2014;55:516–23.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Natural Science Foundation of China (T2321004, 91949202, 82090024, 81873614, 82090021, 81900621, 81970580, 82070753, 82170734, 81800645, 81800643, 22107058); Shandong Provincial Natural Science Foundation, China (ZR2019ZD40, ZR2019MH041, 2023HWYQ-020); The Taishan Scholars Program of Shandong Province, China (tsqn202306074) and Cutting Edge Development Fund of Advanced Medical Research Institute (GYY2023QY01).

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Authors and Affiliations

  1. Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China

    Fu-wen Zuo, Zhi-yong Liu, Ming-wei Wang, Jun-yao Du, Peng-zhong Ding, Hao-ran Zhang, Yu Sun, Xiao-jie Wang, Yan Zhang, Yu-sheng Xie, Ji-chao Wu, Min Liu, Zi-ying Wang & Fan Yi

  2. Department of Pathogenic Biology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China

    Wei Tang

  3. National Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, 250012, China

    Fan Yi

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Contributions

FWZ. conducted the in vivo and in vitro experiments, performed data analysis, and helped write the manuscript. ZYL, MWW, JYD, PZD and HRZ. contributed to the experimental design and performed the in vitro experiments. XJW performed the in vivo animal studies. YS and YZ helped design the experiments. JCW performed confocal microscopy. WT and YSX analyzed the data. FY, ZYW, and ML designed the experiments, interpreted the data, wrote the manuscript, and approved the final version of the manuscript for publication.

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Correspondence to Min Liu, Zi-ying Wang or Fan Yi.

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Zuo, Fw., Liu, Zy., Wang, Mw. et al. CCDC92 promotes podocyte injury by regulating PA28α/ABCA1/cholesterol efflux axis in type 2 diabetic mice. Acta Pharmacol Sin 45, 1019–1031 (2024). https://doi.org/10.1038/s41401-023-01213-4

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