Thiazolidinedione-dependent Activation of Sphingosine Kinase 1 Causes an Anti-fibrotic Effect in Renal Mesangial Cells

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2012 Jan 7

PMID 22221312

Citations 8

Authors

A Koch

A Volzke

C Wunsche

D Meyer zu Heringdorf

A Huwiler

J Pfeilschifter

Affiliations

Soon will be listed here.

Abstract

Background And Purpose: PPARγ agonists [thiazolidinediones (TZDs)] are known to exert anti-fibrotic effects in the kidney. In addition, we previously demonstrated that sphingosine kinase 1 (SK-1) and intracellular sphingosine-1-phosphate (S1P), by reducing the expression of connective tissue growth factor (CTGF), have a protective role in the fibrotic process.

Experimental Approach: Here, we investigated the effect of TZDs on intracellular sphingolipid levels and the transcriptional regulation of SK-1 in mesangial cells to evaluate potential novel aspects of the anti-fibrotic capacity of TZDs.

Key Results: Stimulation with the TZDs, troglitazone and rosiglitazone, led to increased S1P levels in rat mesangial cells. This was paralleled by increased SK-1 activity as a consequence of direct effects of the TZDs on SK-1 expression. GW-9662, a PPARγ antagonist, inhibited the stimulating effect of TZDs on SK-1 mRNA and activity levels and intracellular S1P concentrations. Furthermore, SK-1 up-regulation by TZDs was functionally coupled with lower amounts of pro-fibrotic CTGF. SK-1 inhibition with SKI II almost completely abolished this effect in a dose-dependent manner. Moreover, the CTGF lowering effect of TZDs was fully blocked in MC isolated from SK-1 deficient mice (SK-1(-/-) ) as well as in glomeruli of SK-1(-/-) mice compared with wild-type mice treated with TRO and RSG.

Conclusion And Implications: These data show that TZD-induced SK-1 up-regulation results in lower amounts of CTGF, demonstrating novel facets for the anti-fibrotic effects of this class of drugs.

Citing Articles

Effect of FTY720P on lipid accumulation in HEPG2 cells.

Rida R, Kreydiyyeh S Sci Rep. 2023; 13(1):19716.

PMID: 37953311 PMC: 10641067. DOI: 10.1038/s41598-023-46011-4.

Therapeutic Implications of Ferroptosis in Renal Fibrosis.

Zhang Y, Mou Y, Zhang J, Suo C, Zhou H, Gu M Front Mol Biosci. 2022; 9:890766.

PMID: 35655759 PMC: 9152458. DOI: 10.3389/fmolb.2022.890766.

Resveratrol Inhibits Lipopolysaccharide-Induced Extracellular Matrix Accumulation and Inflammation in Rat Glomerular Mesangial Cells by SphK1/S1P2/NF-κB Pathway.

Gong W, Li J, Chen W, Feng F, Deng Y Diabetes Metab Syndr Obes. 2020; 13:4495-4505.

PMID: 33262625 PMC: 7686914. DOI: 10.2147/DMSO.S278267.

Novel Insights into the Role of HDL-Associated Sphingosine-1-Phosphate in Cardiometabolic Diseases.

Diarte-Anazco E, Mendez-Lara K, Perez A, Alonso N, Blanco-Vaca F, Julve J Int J Mol Sci. 2019; 20(24).

PMID: 31842389 PMC: 6940915. DOI: 10.3390/ijms20246273.

Normalisation of surfactant protein -A and -B expression in the lungs of low birth weight lambs by 21 days old.

Soo J, Orgeig S, McGillick E, Zhang S, McMillen I, Morrison J PLoS One. 2017; 12(9):e0181185.

PMID: 28949968 PMC: 5614422. DOI: 10.1371/journal.pone.0181185.

References

Minucci S, Pelicci P . Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer. 2006; 6(1):38-51. DOI: 10.1038/nrc1779. View

Houtkooper R, Auwerx J . Obesity: New life for antidiabetic drugs. Nature. 2010; 466(7305):443-4. PMC: 3852809. DOI: 10.1038/466443a. View

Riser B, Cortes P, DeNichilo M, Deshmukh P, Chahal P, Mohammed A . Urinary CCN2 (CTGF) as a possible predictor of diabetic nephropathy: preliminary report. Kidney Int. 2003; 64(2):451-8. DOI: 10.1046/j.1523-1755.2003.00130.x. View

Long D, Price K . Sphingosine kinase-1: a potential mediator of renal fibrosis. Kidney Int. 2009; 76(8):815-7. DOI: 10.1038/ki.2009.310. View

Schwalm S, Pfeilschifter J, Huwiler A . Sphingosine kinase 1 is critically involved in nitric oxide-mediated human endothelial cell migration and tube formation. Br J Pharmacol. 2010; 160(7):1641-51. PMC: 2936837. DOI: 10.1111/j.1476-5381.2010.00818.x. View

Schwalm S, Doll F, Romer I, Bubnova S, Pfeilschifter J, Huwiler A . Sphingosine kinase-1 is a hypoxia-regulated gene that stimulates migration of human endothelial cells. Biochem Biophys Res Commun. 2008; 368(4):1020-5. DOI: 10.1016/j.bbrc.2008.01.132. View

Yang T, Michele D, Park J, Smart A, Lin Z, Brosius 3rd F . Expression of peroxisomal proliferator-activated receptors and retinoid X receptors in the kidney. Am J Physiol. 1999; 277(6):F966-73. DOI: 10.1152/ajprenal.1999.277.6.F966. View

Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F . BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med. 2003; 9(7):964-8. DOI: 10.1038/nm888. View

Wang W, Liu F, Chen N . Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists attenuate the profibrotic response induced by TGF-beta1 in renal interstitial fibroblasts. Mediators Inflamm. 2008; 2007:62641. PMC: 2220083. DOI: 10.1155/2007/62641. View

10.

Koch A, Konig B, Stangl G, Eder K . PPAR alpha mediates transcriptional upregulation of novel organic cation transporters-2 and -3 and enzymes involved in hepatic carnitine synthesis. Exp Biol Med (Maywood). 2008; 233(3):356-65. DOI: 10.3181/0706-RM-168. View

11.

Kawai T, Masaki T, Doi S, Arakawa T, Yokoyama Y, Doi T . PPAR-gamma agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-beta. Lab Invest. 2008; 89(1):47-58. DOI: 10.1038/labinvest.2008.104. View

12.

Boor P, Sebekova K, Ostendorf T, Floege J . Treatment targets in renal fibrosis. Nephrol Dial Transplant. 2007; 22(12):3391-407. DOI: 10.1093/ndt/gfm393. View

13.

Melendez A, Gosink M, Allen J, Takacs L . Human sphingosine kinase: molecular cloning, functional characterization and tissue distribution. Gene. 2000; 251(1):19-26. DOI: 10.1016/s0378-1119(00)00205-5. View

14.

Ren S, Babelova A, Moreth K, Xin C, Eberhardt W, Doller A . Transforming growth factor-beta2 upregulates sphingosine kinase-1 activity, which in turn attenuates the fibrotic response to TGF-beta2 by impeding CTGF expression. Kidney Int. 2009; 76(8):857-67. DOI: 10.1038/ki.2009.297. View

15.

Gupta S, Clarkson M, Duggan J, Brady H . Connective tissue growth factor: potential role in glomerulosclerosis and tubulointerstitial fibrosis. Kidney Int. 2000; 58(4):1389-99. DOI: 10.1046/j.1523-1755.2000.00301.x. View

16.

Tachibana K, Yamasaki D, Ishimoto K, Doi T . The Role of PPARs in Cancer. PPAR Res. 2008; 2008:102737. PMC: 2435221. DOI: 10.1155/2008/102737. View

17.

Liu H, Sugiura M, Nava V, Edsall L, Kono K, Poulton S . Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform. J Biol Chem. 2000; 275(26):19513-20. DOI: 10.1074/jbc.M002759200. View

18.

Crean J, Furlong F, Finlay D, Mitchell D, Murphy M, Conway B . Connective tissue growth factor [CTGF]/CCN2 stimulates mesangial cell migration through integrated dissolution of focal adhesion complexes and activation of cell polarization. FASEB J. 2004; 18(13):1541-3. DOI: 10.1096/fj.04-1546fje. View

19.

Huwiler A, Doll F, Ren S, Klawitter S, Greening A, Romer I . Histamine increases sphingosine kinase-1 expression and activity in the human arterial endothelial cell line EA.hy 926 by a PKC-alpha-dependent mechanism. Biochim Biophys Acta. 2006; 1761(3):367-76. DOI: 10.1016/j.bbalip.2006.02.007. View

20.

Dornhofer N, Spong S, Bennewith K, Salim A, Klaus S, Kambham N . Connective tissue growth factor-specific monoclonal antibody therapy inhibits pancreatic tumor growth and metastasis. Cancer Res. 2006; 66(11):5816-27. DOI: 10.1158/0008-5472.CAN-06-0081. View