NDT Advance Access originally published online on May 29, 2008
Nephrology Dialysis Transplantation 2008 23(11):3472-3478; doi:10.1093/ndt/gfn276
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Activation of hypoxia-inducible factors ameliorates hypoxic distal tubular injury in the isolated perfused rat kidney
1 Department of Nephrology and Medical Intensive Care, Charité University Clinic, Berlin, Germany 2 Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA 3 Department of Medicine, Hadassah Hospital, Mt. Scopus and the Hebrew University Medical School, Jerusalem, Israel 4 Departments of Nephrology and Hypertension, University of Erlangen-Nuremberg, Germany 5 FibroGen, Inc., San Francisco, CA, USA
Correspondence and offprint requests to: Samuel N. Heyman, Department of Medicine, Hadassah Hospital, Mt. Scopus, PO Box 24035, Jerusalem 91240, Israel. Tel: +972-2-5844111; Fax: +972-2-5823515; E-mail: heyman{at}cc.huji.ac.il
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Abstract |
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Background. Preconditional activation of HIF with specific prolyl-hydroxylase inhibitors (PHD-I) attenuates proximal tubular injury, induced by warm ischaemia/ reperfusion (Bernhardt, JASN, 2006). Distal tubular damage occurs in humans with acute kidney injury (AKI), in experimental contrast media-induced nephropathy (CIN), as well as in cell-free isolated perfused kidneys (IPKs). Since in the IPK distal tubular damage inversely correlates with HIF activation (Rosenberger, KI, 2005), we explored the potential of PHD-I to improve morpho-functional outcome in this model.
Methods. Male SD rats were randomly given the synthetic PHD-inhibitor FG-4497 (FibroGen®, 50 mg/kg IV) or its vehicle (CTR, n = 10 per group). Six hours later, the right kidney was perfused for 90 min with cell-free oxygenated medium and subsequently perfusion-fixed for morphologic assessment. The left kidney was used for HIF immunostaining.
Results. As compared with CTR kidneys, at 6 h after FG-4497 HIF-
isoforms were markedly up-regulated in all renal zones: HIF-1 in tubules and in papillary interstitial cells (IC), HIF-2 in IC and vascular endothelial cells. FG-4497 treatment resulted in a higher perfusate flow rate (P < 0.04, ANOVA). Tubular injury to medullary thick ascending limbs (mTALs) was significantly attenuated in the treatment versus control group (38.9 ± 7.4% versus 62.7 ± 4.9% of mTALs in the mid-inner stripe (P < 0.02); 23.8 ± 6.8% versus 45.6 ± 7.4% in the innermost zone of the inner stripe (P < 0.05).
Conclusions. These findings illustrate that PHD-I preconditioning attenuates hypoxic distal tubular injury produced in the IPK in the same fashion in which it protects proximal tubules. mTAL conservation may be related to the stabilization of cellular HIF, as well as to preserved endothelial function and microcirculation.
Keywords: HIF-1; HIF-2; hypoxia; medullary thick ascending limb; prolyl-hydroxylase
Received for publication: 1. 2.08
Accepted in revised form: 22. 4.08