Peroxisome proliferator-activated receptor-γ agonist pioglitazone fails to attenuate renal fibrosis caused by unilateral ureteral obstruction in mice

Abstract

Renal tubulointerstitial fibrosis is the common ending of progreβsive renal disease. It is worth developing new ways to stop the progreβs of renal fibrosis. Peroxisome proliferator-activated receptor-γ (PPARγ) agonists have been studied to treat diabetic nephropathy, cisplatin-induced acute renal injury, ischemia reperfusion injury and adriamycin nephropathy. In this study, unilateral ureteral obstruction (UUO) was used to establish a different renal fibrosis model. PPAR? agonist pioglitazone was administrated by oral gavage and saline was used as control. At 7th and 14th day after the operation, mice were sacrificed for fibrosis test and T lymphocytes subsets test. Unexpectedly, through MASSON staining, immunohistochemistry for α-SMA, and Western blotting for a-SMA and PDGFR-β, we found that pioglitazone failed to attenuate renal fibrosis in UUO mice. However, flow cytometry showed that pioglitazone down-regulated Th1 cells, and up-regulated Th2 cells, Th17 cells and Treg cells. But the Th17/Treg ratio had no significant change by pioglitazone. Real-time PCR results showed that TGF-β and MCP-1 had no significant changes, at the same time, CD4⁺ T cells associated cytokines were partially regulated by pioglitazone pretreatment. Taken together, pioglitazone failed to suppress renal fibrosis progression caused by UUO.

Keywords

renal fibrosis / unilateral ureteral obstruction / PPAR-γ / T lymphocyte

References

[1] ZeisbergM, NeilsonEG. Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol, 2010, 21(11): 1819-1834 PMID: 20864689

[2] NangakuM. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure. J Am Soc Nephrol, 2006, 17(1): 17-25 PMID: 16291837

[3] ChungAC, LanHY. Chemokines in renal injury. J Am Soc Nephrol, 2011, 22(5): 802-809 PMID: 21474561

[4] PiccottiJR, LiK, ChanSY, et al. . Cytokine regulation of chronic cardiac allograft rejection: evidence against a role for Th1 in the disease process. Transplantation, 1999, 67(12): 1548-1555 PMID: 10401761

[5] KimSM, LeeSH, LeeA, et al. . Targeting T helper 17 by mycophenolate mofetil attenuates diabetic nephropathy progression. Transpl Res, 2015

[6] SakaiN, WadaT. T Helper 2 cytokine signaling in bone marrow-derived fibroblasts: A target for renal fibrosis. J Am Soc Nephrol, 2015, 26(12): 2896-2898 PMID: 26032812

[7] JunC, KeW, QingshuL, et al. . Protective effect of CD4(+)CD25(high)CD127(low) regulatory T cells in renal ischemia-reperfusion injury. Cell Immunol, 2014, 289(1–2): 106-111 PMID: 24754976

[8] TapmeierTT, FearnA, BrownK, et al. . Pivotal role of CD4+ T cells in renal fibrosis following ureteric obstruction. Kidney Int, 2010, 78(4): 351-362 PMID: 20555323

[9] LiuL, KouP, ZengQ, et al. . CD4+ T lymphocytes, especially Th2 cells, contribute to the progress of renal fibrosis. Am J Nephrol, 2012, 36(4): 386-396 PMID: 23052013

[10] LinFJ, JiangGR, ShanJP, et al. . Imbalance of regulatory T cells to Th17 cells in IgA nephropathy. Scand J Clin Lab Invest, 2012, 72(3): 221-229 PMID: 22276947

[11] WenbinZ, GuojunG. Resveratrol ameliorates diabetes-induced renal damage through regulating the expression of TGF-beta1, collagen IV and Th17/Treg-related cytokines in rats. West Indian Med J, 2014, 63(1): 20-25 PMCID: 4655635 PMID: 25303188

[12] LiY, ShiY, HuangZ, et al. . CNI induced Th17/Treg imbalance and susceptibility to renal dysfunction in renal transplantation. Int Immunopharmacol, 2011, 11(12): 2033-2038 PMID: 21911083

[13] CariouB, CharbonnelB, StaelsB. Thiazolidinediones and PPARgamma agonists: time for a reassessment. Trends Endocrinol Metab, 2012, 23(5): 205-215 PMID: 22513163

[14] LeeYJ, HanHJ. Troglitazone ameliorates high glucose-induced EMT and dysfunction of SGLTs through PI3K/Akt, GSK-3beta, Snail1, and beta-catenin in renal proximal tubule cells. Am J Physiol Renal Physiol, 2010, 298(5): F1263-F1275 PMID: 20015942

[15] PistroschF, PassauerJ, HerbrigK, et al. . Effect of thiazolidinedione treatment on proteinuria and renal hemodynamic in type 2 diabetic patients with overt nephropathy. Horm Metab Res, 2012, 44(12): 914-918 PMID: 22723267

[16] HuangKC, CherngYG, ChenLJ, et al. . Rosiglitazone is effective to improve renal damage in type-1-like diabetic rats. Horm Metab Res, 2014, 46(4): 240-244 PMID: 24136780

[17] AgarwalR, SahaC, BattiwalaM, et al. . A pilot randomized controlled trial of renal protection with pioglitazone in diabetic nephropathy. Kidey Int, 2005, 68(1): 285-292

[18] SchneiderCA, FerranniniE, DefronzoR, et al. . Effect of pioglitazone on cardiovascular outcome in diabetes and chronic kidney disease. J Am Soc Nephrol, 2008, 19(1): 182-187 PMCID: 2391042 PMID: 18057215

[19] YangHC, DeleuzeS, ZuoY, et al. . The PPARgamma agonist pioglitazone ameliorates aging-related progressive renal injury. J Am Soc Nephrol, 2009, 20(11): 2380-2388 PMCID: 2799181 PMID: 19797472

[20] JesseCR, BortolattoCF, WilhelmEA, et al. . The peroxisome proliferator-activated receptor-gamma agonist pioglitazone protects against cisplatin-induced renal damage in mice. J Appl Toxicol, 2014, 34(1): 25-32 PMID: 22987311

[21] HuH, ZouC, XiX, et al. . Protective effects of pioglitazone on renal ischemia-reperfusion injury in mice. J Surg Res, 2012, 178(1): 460-465 PMID: 22507688

[22] HigashiK, OdaT, KushiyamaT, et al. . Additive antifibrotic effects of pioglitazone and candesartan on experimental renal fibrosis in mice. Nephrology (Carlton), 2010, 15(3): 327-335

[23] HanJY, KimYJ, KimL, et al. . PPARgamma agonist and angiotensin II receptor antagonist ameliorate renal tubulointerstitial fibrosis. J Korean Med Sci, 2010, 25(1): 35-41 PMCID: 2799997 PMID: 20052345

[24] OrasanuG, ZiouzenkovaO, DevchandPR, et al. . The peroxisome proliferator-activated receptor-gamma agonist pioglitazone represses inflammation in a peroxisome proliferator-activated receptor-alpha-dependent manner in vitro and in vivo in mice. J Am Coll Cardiol, 2008, 52(10): 869-881 PMCID: 2633943 PMID: 18755353

[25] MartensFM, RabelinkTJ, OpTRJ, et al. . TNF-alpha induces endothelial dysfunction in diabetic adults, an effect reversible by the PPAR-gamma agonist pioglitazone. Eur Heart J, 2006, 27(13): 1605-1609 PMID: 16762982

[26] LeaS, PlumbJ, MetcalfeH, et al. . The effect of peroxisome proliferator-activated receptor-gamma ligands on in vitro and in vivo models of COPD. Eur Respir J, 2014, 43(2): 409-420 PMID: 23794466

[27] CipollettaD, FeuererM, LiA, et al. . PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature, 2012, 486(7404): 549-553 PMCID: 3387339 PMID: 22722857

[28] BuntSK, MohrAM, BaileyJM, et al. . Rosiglitazone and Gemcitabine in combination reduces immune suppression and modulates T cell populations in pancreatic cancer. Cancer Immunol Immunother, 2013, 62(2): 225-236 PMID: 22864396

[29] SchaeferKL, DenevichS, MaC, et al. . Intestinal antiinflammatory effects of thiazolidenedione peroxisome proliferator-activated receptor-gamma ligands on T helper type 1 chemokine regulation include nontranscriptional control mechanisms. Inflamm Bowel Dis, 2005, 11(3): 244-252 PMID: 15735430

[30] OchodnickyP, MesarosovaL, CerneckaH, et al. . Pioglitazone, a PPARgamma agonist, provides comparable protection to angiotensin converting enzyme inhibitor ramipril against adriamycin nephropathy in rat. Eur J Pharmacol, 2014, 730: 51-60 PMID: 24582928

[31] ShappellS, GurpinarT, LechagoJ, et al. . Chronic obstructive uropathy in severe combined immunodeficient (SCID) mice: lymphocyte infiltration is not required for progressive tubulointerstitial injury. J Am Soc Nephrol, 1998, 9(6): 1008-1017 PMID: 9621283

[32] ChengP, ZhangY, HuangH, et al. . Association between CCR6 and rheumatoid arthritis: a meta-analysis. Int J Clin Exp Med, 2015, 8(4): 5388-5396 PMCID: 4483986 PMID: 26131115

[33] ChengP, SunXY, YinDL, et al. . Nanog down-regulates the Wnt signaling pathway via β-catenin phosphorylation during epidermal stem cell proliferation and differentiation. Cell Biosci, 2015, 5: 5 PMCID: 4429823 PMID: 25973172

[34] HenriS, ChevillardC, MerganiA, et al. . Cytokine regulation of periportal fibrosis in humans infected with Schistosoma mansoni: IFN-gamma is associated with protection against fibrosis and TNF-alpha with aggravation of disease. J Immunol, 2002, 169(2): 929-936 PMID: 12097398

[35] SaitoA, OkazakiH, SugawaraI, et al. . Potential action of IL-4 and IL-13 as fibrogenic factors on lung fibroblasts in vitro. Int Arch Allergy Immunol, 2003, 132(2): 168-176 PMID: 14600429