Journal Article

Activation of hypoxia-inducible factors ameliorates hypoxic distal tubular injury in the isolated perfused rat kidney

Christian Rosenberger, Seymour Rosen, Ahuva Shina, Ulrich Frei, Kai-Uwe Eckardt, Lee A. Flippin, Michael Arend, Stephen J. Klaus and Samuel N. Heyman

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 23, issue 11, pages 3472-3478
Published in print November 2008 | ISSN: 0931-0509
Published online May 2008 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfn276
Activation of hypoxia-inducible factors ameliorates hypoxic distal tubular injury in the isolated perfused rat kidney

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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-α isoforms were markedly up-regulated in all renal zones: HIF-1α in tubules and in papillary interstitial cells (IC), HIF-2α 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-1α; HIF-2α; hypoxia; medullary thick ascending limb; prolyl-hydroxylase

Journal Article.  3463 words.  Illustrated.

Subjects: Nephrology

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