FR167653 improves renal recovery and decreases inflammation and fibrosis after renal ischemia reperfusion injury Jerome Cau, MD, Frederic Favreau, PhD,

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FR167653 improves renal recovery and decreases inflammation and fibrosis after renal ischemia reperfusion injury Jerome Cau, MD, Frederic Favreau, PhD, Keqiang Zhang, PhD, Guillaume Febrer, MD, Gilles Regnault de la Motte, MD, Jean-Baptiste Ricco, MD, Jean-Michel Goujon, MD, PhD, Thierry Hauet, PhD Journal of Vascular Surgery Volume 49, Issue 3, Pages 728-740 (March 2009) DOI: 10.1016/j.jvs.2008.09.056 Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 1 Chemical structure of FR167653: 1-[7-(4-fluorophenyl)-1,2,3,4-tetrahydro-8-(4-pyridyl)pyrazolo[5,1-c][1,2,4]triazin-2-yl]-2-phenylethanedione sulfate monohydrate. Journal of Vascular Surgery 2009 49, 728-740DOI: (10.1016/j.jvs.2008.09.056) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 2 Effect of FR167653 (FR) treatment on renal function. Serum creatinine was determined as a marker of renal function in the experimental groups after different warm ischemia (WI) and compared with a control group and an uninephrectomized (Unif) group. Serum creatinine was measured before and at days 1, 2, 3, 7, and 14 and at week 1 and 12 after WI induction. The values reported are the mean ± standard error of the mean. 1/2N×90, 90 minutes of unilateral renal clamping after contralateral nephrectomy; WIuni90, unilateral WI for 90 minutes. *P < .05 FR-treated groups vs no-FR-treated groups, °P < .05 FR-treated groups vs no-FR-treated groups, and #FR1/2N×90 vs 1/2N×90. Journal of Vascular Surgery 2009 49, 728-740DOI: (10.1016/j.jvs.2008.09.056) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 3 Effect of FR167653 (FR) treatment on proteinuria. Proteinuria was determined in urine as a marker of renal injury in the different experimental groups after different warm ischemia (WI) and compared with control group and uninephrectomized (Unif) group. The values reported are the mean ± standard error of the mean.*P < .05, FR-treated groups vs no-FR-treated groups. 1/2N×90, 90 minutes of unilateral renal clamping after contralateral nephrectomy; WIuni90, unilateral warm ischemia for 90 minutes. Journal of Vascular Surgery 2009 49, 728-740DOI: (10.1016/j.jvs.2008.09.056) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 4 Effect of FR167653 (FR) treatment on renal tubular injury. Tubular injury was defined as (A) tubular epithelium necrosis, (B) intratubular debris, and (C) cell loss. The no-FR-treated groups have very severe tubular injury in all categories, whereas the FR-treated groups showed mild injury accompanied with a fast and efficient repair process as shown by evaluation of tubular injury at week 12. The values reported are the mean ± standard error of the mean. 1/2N×90, 90 minutes of unilateral renal clamping after contralateral nephrectomy; Unif, uninephrectomized group; WIuni90, unilateral warm ischemia for 90 minutes.*P < .05, FR-treated groups vs no-FR-treated groups. Journal of Vascular Surgery 2009 49, 728-740DOI: (10.1016/j.jvs.2008.09.056) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 5 Effect of FR167653 (FR) on renal tubular injury after warm ischemia (WI) and reperfusion. The black arrow points to brush border (bb) integrity. A, Uninephrectomy (Unif) group. B, Control group. C to F, Groups not treated with FR167653: WI for 90 minutes (WI90), unilateral renal clamping after contralateral nephrectomy (1/2N×90), unilateral WI for 90 minutes (WIuni90), and WIuni90 contralateral kidneys. G to J, Groups treated with FR: FRWI90, FR1/2N×90, FRWIuni90, and FRWIuni90 contralateral kidneys (original magnification ×200; scale bar, 200 μm). Journal of Vascular Surgery 2009 49, 728-740DOI: (10.1016/j.jvs.2008.09.056) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 6 Effect of FR167653 (FR) treatment on the onset of tubulointerstitial fibrosis. Upper Panel, The percentage of kidney areas displaying interstitial fibrosis stained with picrosirius was measured during several weeks after warm ischemia within kidneys. The values reported are the mean ± standard error of the mean. *P < .05, FR-treated groups vs no-FR-treated groups. Lower Panel, Immunostaining for picrosirius in the different experimental groups. A and B, Uninephrectomy (Unif) group and control group, respectively. C to F, no-FR167653-treated groups: warm ischemia (WI) for 90 minutes (WI90), 90 minutes of unilateral (uni) renal clamping after contralateral nephrectomy (1/2N×90), WIuni90, and WIuni90 contralateral kidneys. G to J, FR-treated groups: FRWI90, FR1/2N×90, FRWIuni90, and FRWIuni90 contralateral kidneys (original magnification ×200; scale bar, 200 μm). Journal of Vascular Surgery 2009 49, 728-740DOI: (10.1016/j.jvs.2008.09.056) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 7 Effect of FR167653 (FR) treatment on tubular atrophy at 3 months (See Methods for details). The values reported are the mean ± standard error of the mean. *P < .05, FR-treated groups vs no-FR-treated groups. 1/2N×90, 90 minutes of unilateral (uni) renal clamping after contralateral nephrectomy; WI, warm ischemia; Unif, Uninephrectomy. Journal of Vascular Surgery 2009 49, 728-740DOI: (10.1016/j.jvs.2008.09.056) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 8 Effect of FR167653 (FR) treatment on inflammation in post-reperfused kidney. Upper Panel, The number of positively stained cells per surface area was counted on biopsy samples from experimental groups at 1 and 6 weeks and at 3 months. FR treatment reduced CD3-positive cells staining compared with no FR treatment. Lower Panel, Immunostaining for CD3-positive cells at 3 months (black arrow) in the different experimental groups, uninephrectomy (Unif) group, and control group, respectively. No-FR167653-treated groups: WI90, 90 minutes of unilateral (uni) renal clamping after contralateral nephrectomy (1/2N×90), 90 minutes of unilateral warm ischemia (WIuni90), and WIuni90 contralateral kidneys. FR-treated groups: FRWI90, FR1/2N×90, FRWIuni90, and FRWIuni90 contralateral kidneys (original magnification ×200; scale bar, 200 μm). Journal of Vascular Surgery 2009 49, 728-740DOI: (10.1016/j.jvs.2008.09.056) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 9 Effect of FR167653 (FR) treatment on tumor necrosis factor-α (TNF-α) protein, messenger RNA expression, and on phosphorylated p38-mitogen activated protein kinase (MAPK) within renal tissue from different experimental conditions. A, Representative immunoblots of TNF-α from the different experimental groups. B, Quantification of renal protein. FR treatment reduced TNF-α expression. C, The ratio of TNF-α. D, Quantification of phosphorylated p38-MAPK (phospho-p38)/total p38-MAPK (total-p38) is presented. E, Representative immunoblot of phospho-p38 and total p-38 respectively. The values reported are the mean ± standard error of the mean. 1/2N×90, 90 minutes of unilateral renal clamping after contralateral nephrectomy; Unif, uninephrectomized group; WIuni90, unilateral warm ischemia for 90 minutes. *P < .05, FR-treated groups vs no-FR-treated groups, °P < .05 WI and 1/2N×90 groups vs control and Unif groups. Journal of Vascular Surgery 2009 49, 728-740DOI: (10.1016/j.jvs.2008.09.056) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 10 Effect of FR167653 (FR) treatment on (Left) interleukin-1 (IL-1) and (Right) tumor necrosis factor-α (TNF-α) release. FR167653 treatment reduced TNF-α and IL-1 release. The values reported are the mean ± standard error of the mean. 1/2N×90, 90 minutes of unilateral renal clamping after contralateral nephrectomy; Unif, uninephrectomized group; WIuni90, unilateral warm ischemia for 90 minutes. *P < .05 FR-treated groups vs no-FR-treated groups. Journal of Vascular Surgery 2009 49, 728-740DOI: (10.1016/j.jvs.2008.09.056) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions

Fig 11 Quantification of circulating tumor necrosis factor-α (TNF-α) is presented. The values reported are the mean ± standard error of the mean. 1/2N×90, 90 minutes of unilateral renal clamping after contralateral nephrectomy; Unif, uninephrectomized group; WIuni90, unilateral warm ischemia for 90 minutes. *P < .05, groups treated with FR167653 (FR) vs untreated groups, °P < .05 WI and 1/2N×90 groups vs control and Unif groups. Journal of Vascular Surgery 2009 49, 728-740DOI: (10.1016/j.jvs.2008.09.056) Copyright © 2009 The Society for Vascular Surgery Terms and Conditions