Angiopoietin-Like-4, a Potential Target of Tacrolimus, Predicts Earlier Podocyte Injury in Minimal Change Disease

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2015 Sep 10

PMID 26352670

Citations 14

Authors

Jian-Si Li

Xiao Chen

Lei Peng

Shi-Yao Wei

Shi-Lei Zhao

Tian-Tian Diao

Yi-Xin He

Fang Liu

Qiu-Ju Wei

Qing-Fang Zhang

Bing Li

Affiliations

Soon will be listed here.

Abstract

Podocyte injury plays central roles in proteinuria and kidney dysfunction, therefore, identifying specific biomarker to evaluate earlier podocyte injury is highly desirable. Podocyte-secreted angiopoietin-like-4 (Angptl4) mediates proteinuria in different types of podocytopathy. In the present study, we established an experimental minimal change disease (MCD) rat model, induced by adriamycin (ADR) and resulted in definite podocyte injury, to identify the dynamic changes in Angptl4 expression. We also investigated the direct effects of tacrolimus on Angptl4 and podocyte repair. We determined that the glomerular Angptl4 expression was rapidly upregulated and reached a peak earlier than desmin, an injured podocyte marker, in the ADR rats. Furthermore, this upregulation occurred prior to heavy proteinuria and was accompanied by increased urinary Angptl4. We observed that the Angptl4 upregulation occurred only when podocyte was mainly damaged since we didn't observe little Angptl4 upregulation in MsPGN patients. In addition, we observed the glomerular Angptl4 mainly located in injured podocytes rather than normal podocytes. Moreover, we found that tacrolimus treatment significantly promoted podocyte repair and reduced glomerular and urinary Angptl4 expression at an earlier stage with a significant serum Angptl4 upregulation. And similar results were confirmed in MCD patients. In conclusion, this study represents the first investigation to demonstrate that Angptl4 can predict podocyte injury at earlier stages in MCD and the identification of earlier podocyte injury biomarkers could facilitate the prompt diagnosis and treatment of patients with podocytopathy, as well as determination of the prognosis and treatment efficacy in these diseases.

Citing Articles

Advancing the clinical assessment of glomerular podocyte pathology in kidney biopsies via super-resolution microscopy and angiopoietin-like 4 staining.

Liu X, Wang S, Liu G, Wang Y, Shang S, Zou G Theranostics. 2025; 15(3):784-803.

PMID: 39776814 PMC: 11700855. DOI: 10.7150/thno.101498.

TRPC6 knockdown-mediated ERK1/2 inactivation alleviates podocyte injury in minimal change disease via upregulating Lon peptidase 1.

Ma J, Ren L, Su Q, Lv X, Sun M, Wei Y Ren Fail. 2024; 46(2):2431150.

PMID: 39566913 PMC: 11580150. DOI: 10.1080/0886022X.2024.2431150.

Cytoskeleton Rearrangement in Podocytopathies: An Update.

Ma S, Qiu Y, Zhang C Int J Mol Sci. 2024; 25(1).

PMID: 38203817 PMC: 10779434. DOI: 10.3390/ijms25010647.

Efficacy and safety of tacrolimus-based treatment for non-rapidly progressive IgA nephropathy.

Zhao L, Yang Y, Xu H, Leng W, Xu G Front Pharmacol. 2023; 14:1189608.

PMID: 37274107 PMC: 10232819. DOI: 10.3389/fphar.2023.1189608.

Serum and urine ANGPTL8 expression levels are associated with hyperlipidemia and proteinuria in primary nephrotic syndrome.

Li Y, Liu Q, Kang C, Cui W, Xu Z, Zhong F BMC Nephrol. 2021; 22(1):130.

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References

Fan L, Liu Q, Liao Y, Li Z, Ji Y, Yang Z . Tacrolimus is an alternative therapy option for the treatment of adult steroid-resistant nephrotic syndrome: a prospective, multicenter clinical trial. Int Urol Nephrol. 2012; 45(2):459-68. DOI: 10.1007/s11255-012-0205-1. View

Gulati A, Sinha A, Gupta A, Kanitkar M, Sreenivas V, Sharma J . Treatment with tacrolimus and prednisolone is preferable to intravenous cyclophosphamide as the initial therapy for children with steroid-resistant nephrotic syndrome. Kidney Int. 2012; 82(10):1130-5. DOI: 10.1038/ki.2012.238. View

Clement L, Mace C, Avila-Casado C, Joles J, Kersten S, Chugh S . Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome. Nat Med. 2013; 20(1):37-46. PMC: 4114723. DOI: 10.1038/nm.3396. View

Peng L, Ma J, Cui R, Chen X, Wei S, Wei Q . The calcineurin inhibitor tacrolimus reduces proteinuria in membranous nephropathy accompanied by a decrease in angiopoietin-like-4. PLoS One. 2014; 9(8):e106164. PMC: 4148427. DOI: 10.1371/journal.pone.0106164. View

Ma J, Chen X, Li J, Peng L, Wei S, Zhao S . Upregulation of podocyte-secreted angiopoietin-like-4 in diabetic nephropathy. Endocrine. 2014; 49(2):373-84. DOI: 10.1007/s12020-014-0486-5. View

Yaoita E, Kawasaki K, Yamamoto T, KIHARA I . Variable expression of desmin in rat glomerular epithelial cells. Am J Pathol. 1990; 136(4):899-908. PMC: 1877632. View

Glynne R, Akkaraju S, Healy J, Rayner J, Goodnow C, Mack D . How self-tolerance and the immunosuppressive drug FK506 prevent B-cell mitogenesis. Nature. 2000; 403(6770):672-6. DOI: 10.1038/35001102. View

Yoon J, Chickering T, Rosen E, Dussault B, Qin Y, Soukas A . Peroxisome proliferator-activated receptor gamma target gene encoding a novel angiopoietin-related protein associated with adipose differentiation. Mol Cell Biol. 2000; 20(14):5343-9. PMC: 85983. DOI: 10.1128/MCB.20.14.5343-5349.2000. View

Kersten S, Mandard S, Tan N, Escher P, Metzger D, Chambon P . Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene. J Biol Chem. 2000; 275(37):28488-93. DOI: 10.1074/jbc.M004029200. View

10.

Hoshi S, Shu Y, Yoshida F, Inagaki T, Sonoda J, Watanabe T . Podocyte injury promotes progressive nephropathy in zucker diabetic fatty rats. Lab Invest. 2002; 82(1):25-35. DOI: 10.1038/labinvest.3780392. View

11.

Belanger A, Lu H, Date T, Liu L, Vincent K, Akita G . Hypoxia up-regulates expression of peroxisome proliferator-activated receptor gamma angiopoietin-related gene (PGAR) in cardiomyocytes: role of hypoxia inducible factor 1alpha. J Mol Cell Cardiol. 2002; 34(7):765-74. DOI: 10.1006/jmcc.2002.2021. View

12.

Yoshida K, Shimizugawa T, Ono M, Furukawa H . Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase. J Lipid Res. 2002; 43(11):1770-2. DOI: 10.1194/jlr.c200010-jlr200. View

13.

Habashy D, Hodson E, Craig J . Interventions for steroid-resistant nephrotic syndrome: a systematic review. Pediatr Nephrol. 2003; 18(9):906-12. DOI: 10.1007/s00467-003-1207-0. View

14.

Ge H, Yang G, Yu X, Pourbahrami T, Li C . Oligomerization state-dependent hyperlipidemic effect of angiopoietin-like protein 4. J Lipid Res. 2004; 45(11):2071-9. DOI: 10.1194/jlr.M400138-JLR200. View

15.

Bertani T, Poggi A, Pozzoni R, Delaini F, Sacchi G, Thoua Y . Adriamycin-induced nephrotic syndrome in rats: sequence of pathologic events. Lab Invest. 1982; 46(1):16-23. View

16.

Okuda S, Oh Y, Tsuruda H, Onoyama K, Fujimi S, Fujishima M . Adriamycin-induced nephropathy as a model of chronic progressive glomerular disease. Kidney Int. 1986; 29(2):502-10. DOI: 10.1038/ki.1986.28. View

17.

Mundel P, Heid H, Mundel T, Kruger M, Reiser J, Kriz W . Synaptopodin: an actin-associated protein in telencephalic dendrites and renal podocytes. J Cell Biol. 1997; 139(1):193-204. PMC: 2139823. DOI: 10.1083/jcb.139.1.193. View

18.

Orth S, Ritz E . The nephrotic syndrome. N Engl J Med. 1998; 338(17):1202-11. DOI: 10.1056/NEJM199804233381707. View

19.

Li B, Morioka T, Uchiyama M, Oite T . Bone marrow cell infusion ameliorates progressive glomerulosclerosis in an experimental rat model. Kidney Int. 2006; 69(2):323-30. DOI: 10.1038/sj.ki.5000083. View

20.

Kitahara K, Kawai S . Cyclosporine and tacrolimus for the treatment of rheumatoid arthritis. Curr Opin Rheumatol. 2007; 19(3):238-45. DOI: 10.1097/BOR.0b013e328099af80. View