Tacrolimus Protects Podocytes from Injury in Lupus Nephritis Partly by Stabilizing the Cytoskeleton and Inhibiting Podocyte Apoptosis

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2015 Jul 11

PMID 26161538

Citations 40

Authors

Ruyi Liao

Qinghua Liu

Zhihua Zheng

Jinjin Fan

Wenxing Peng

Qingyu Kong

Huijuan He

Shicong Yang

Wenfang Chen

Xueqing Tang

Xueqing Yu

Affiliations

Soon will be listed here.

Abstract

Objective: Several studies have reported that tacrolimus (TAC) significantly reduced proteinuria in lupus nephritis (LN) patients and mouse models. However, the mechanism for this effect remains undetermined. This study explored the mechanism of how TAC protects podocytes from injury to identify new targets for protecting renal function.

Methods: MRL/lpr mice were given TAC at a dosage of 0.1 mg/kg per day by intragastric administration for 8 weeks. Urine and blood samples were collected. Kidney sections (2 μm) were stained with hematoxylin-eosin (HE), periodic acid-Schiff base (PAS) and Masson's trichrome stain. Mouse podocyte cells (MPC5) were treated with TAC and/or TGF-β1 for 48 h. The mRNA levels and protein expression of synaptopodin and Wilms' tumor 1 (WT1) were determined by real-time PCR, Western blotting and/or immunofluorescence, respectively. Flow cytometry was used to detect cell apoptosis with annexin V. Podocyte foot processes were observed under transmission electron microscopy. IgG and C3 deposition were assessed with immunofluorescence assays and confocal microscopy.

Results: Synaptopodin expression significantly decreased in MRL/lpr disease control mice, accompanied by increases in 24-h proteinuria, blood urea nitrogen, and serum creatinine. TAC, however, reduced proteinuria, improved renal function, attenuated renal pathology, restored synaptopodin expression and preserved podocyte numbers. In MPC5 cells, TGF-β1 enhanced F-actin damage in podocytes and TAC stabilized it. TAC also decreased TGF-β1-induced podocyte apoptosis in vitro and inhibited foot process fusion in MRL/lpr mice. In addition, our results also showed TAC inhibited glomerular deposition of IgG and C3.

Conclusion: This study demonstrated that TAC reduced proteinuria and preserved renal function in LN through protecting podocytes from injury partly by stabilizing podocyte actin cytoskeleton and inhibiting podocyte apoptosis.

Citing Articles

FDA-approved drugs featuring macrocycles or medium-sized rings.

Du Y, Semghouli A, Wang Q, Mei H, Kiss L, Baecker D Arch Pharm (Weinheim). 2025; 358(1):e2400890.

PMID: 39865335 PMC: 11771699. DOI: 10.1002/ardp.202400890.

The Ca-actin-cytoskeleton axis in podocytes is an important, non-immunologic target of immunosuppressive therapy in proteinuric kidney diseases.

Hackl A, Weber L Pediatr Nephrol. 2025; .

PMID: 39856247 DOI: 10.1007/s00467-025-06670-z.

The Role of Podocytes in Lupus Pathology.

Maeda K, Abdi R, Tsokos G Curr Rheumatol Rep. 2024; 27(1):10.

PMID: 39731699 DOI: 10.1007/s11926-024-01175-4.

Effect of tacrolimus with mycophenolate mofetil or cyclophosphamide on the renal response in systemic lupus erythematosus patients.

Sun S, Zhang X, Guo Q, Tang X, Shen W, Liang J BMC Rheumatol. 2024; 8(1):68.

PMID: 39695907 PMC: 11654433. DOI: 10.1186/s41927-024-00439-x.

Mechanism of tacrolimus in the treatment of lupus nephritis.

Wang M, Zhou J, Niu Q, Wang H Front Pharmacol. 2024; 15:1331800.

PMID: 38774214 PMC: 11106426. DOI: 10.3389/fphar.2024.1331800.

References

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

Olin A, Morgelin M, Truedsson L, Sturfelt G, Bengtsson A . Pathogenic mechanisms in lupus nephritis: Nucleosomes bind aberrant laminin β1 with high affinity and colocalize in the electron-dense deposits. Arthritis Rheumatol. 2014; 66(2):397-406. DOI: 10.1002/art.38250. View

Srivastava T, Garola R, Whiting J, Alon U . Synaptopodin expression in idiopathic nephrotic syndrome of childhood. Kidney Int. 2001; 59(1):118-25. DOI: 10.1046/j.1523-1755.2001.00472.x. View

Fornoni A, Li H, Foschi A, Striker G, Striker L . Hepatocyte growth factor, but not insulin-like growth factor I, protects podocytes against cyclosporin A-induced apoptosis. Am J Pathol. 2001; 158(1):275-80. PMC: 1850272. DOI: 10.1016/S0002-9440(10)63966-1. View

Kanemoto K, Takahashi S, Shu Y, Usui J, Tomari S, Yan K . Variable expression of podocyte-related markers in the glomeruloid bodies in Wilms tumor. Pathol Int. 2003; 53(9):596-601. DOI: 10.1046/j.1440-1827.2003.01526.x. View

White K, Bilous R . Estimation of podocyte number: a comparison of methods. Kidney Int. 2004; 66(2):663-7. DOI: 10.1111/j.1523-1755.2004.00787.x. View

Kino T, Hatanaka H, Miyata S, Inamura N, Nishiyama M, Yajima T . FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo). 1987; 40(9):1256-65. DOI: 10.7164/antibiotics.40.1256. View

Suzuki N, Sakane T, Tsunematsu T . Effects of a novel immunosuppressive agent, FK506, on human B cell activation. Clin Exp Immunol. 1990; 79(2):240-5. PMC: 1534763. DOI: 10.1111/j.1365-2249.1990.tb05185.x. View

Quinn D, Fennell J, Sheils O, Gaffney E, Feighery C . Effect of cyclosporin on immune complex deposition in murine glomerulonephritis. Immunology. 1991; 72(4):550-4. PMC: 1384376. View

10.

Entani C, Izumino K, Iida H, Fujita M, Asaka M, Takata M . Effect of a novel immunosuppressant, FK506, on spontaneous lupus nephritis in MRL/MpJ-lpr/lpr mice. Nephron. 1993; 64(3):471-5. DOI: 10.1159/000187375. View

11.

Thompson C . Apoptosis in the pathogenesis and treatment of disease. Science. 1995; 267(5203):1456-62. DOI: 10.1126/science.7878464. View

12.

Yamamoto T, Noble N, Cohen A, Nast C, Hishida A, Gold L . Expression of transforming growth factor-beta isoforms in human glomerular diseases. Kidney Int. 1996; 49(2):461-9. DOI: 10.1038/ki.1996.65. View

13.

Mundel P, Reiser J, Kriz W . Induction of differentiation in cultured rat and human podocytes. J Am Soc Nephrol. 1997; 8(5):697-705. DOI: 10.1681/ASN.V85697. View

14.

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

15.

Lotem J, Sachs L . Different mechanisms for suppression of apoptosis by cytokines and calcium mobilizing compounds. Proc Natl Acad Sci U S A. 1998; 95(8):4601-6. PMC: 22536. DOI: 10.1073/pnas.95.8.4601. View

16.

Walter D, Haendeler J, Galle J, Zeiher A, Dimmeler S . Cyclosporin A inhibits apoptosis of human endothelial cells by preventing release of cytochrome C from mitochondria. Circulation. 1998; 98(12):1153-7. DOI: 10.1161/01.cir.98.12.1153. View

17.

Zhao Z, Weinstein E, Tuzova M, Davidson A, Mundel P, Marambio P . Cross-reactivity of human lupus anti-DNA antibodies with alpha-actinin and nephritogenic potential. Arthritis Rheum. 2005; 52(2):522-30. DOI: 10.1002/art.20862. View

18.

Shankland S . The podocyte's response to injury: role in proteinuria and glomerulosclerosis. Kidney Int. 2006; 69(12):2131-47. DOI: 10.1038/sj.ki.5000410. View

19.

Faul C, Donnelly M, Merscher-Gomez S, Chang Y, Franz S, Delfgaauw J . The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med. 2008; 14(9):931-8. PMC: 4109287. DOI: 10.1038/nm.1857. View

20.

Li X, Li H, Ye H, Li Q, He X, Zhang X . Tacrolimus therapy in adults with steroid- and cyclophosphamide-resistant nephrotic syndrome and normal or mildly reduced GFR. Am J Kidney Dis. 2009; 54(1):51-8. DOI: 10.1053/j.ajkd.2009.02.018. View