Evidence of Tubular Hypoxia in the Early Phase in the Remnant Kidney Model

Krissanapong Manotham, Tetsuhiro Tanaka, Makiko Matsumoto, Takamoto Ohse, Toshio Miyata, Reiko Inagi, Kiyoshi Kurokawa, Toshiro Fujita, Masaomi Nangaku

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187 Citations (Scopus)

Abstract

The remnant kidney model is a mainstay in the study of progressive renal disease. The earliest changes in this model result from glomerular hemodynamic alterations. Given that progressive renal disease is the result of subsequent interstitial damage initiated by undetermined pathogenic factors, the authors investigated the role of hypoxia as a pathogenic factor in tubulointerstitial damage after renal ablation in rats. Cortical tissue hypoxia in the early phase (4 and 7 d) in remnant kidney rats, sham-operated rats, and animals treated with the angiotensin II receptor blocker (ARB) olmesartan (10 mg/kg per d) was assessed by uptake of a hypoxic probe, pimonidazole, expression of HIF-1α, and by increased transcription of hypoxia-responsive genes. Physiologic perfusion status of the postglomerular peritubular capillary network was evaluated by lectin perfusion and Hoechst 33342 diffusion techniques. Results showed that the number of hypoxic tubules was markedly increased 4 and 7 d after nephron loss. These findings antedated any histologic evidence of tubulointerstitial damage. The hypoxic state persisted until interstitial damage developed. These results were confirmed using HIF-1α immunoprecipitation and increase of hypoxia-responsive genes. Pathologic studies of the vasculature demonstrated significant functional changes that generated a hypoxic milieu. ARB treatment prevented vascular changes and ameliorated tubular hypoxia. These results suggest that the initial tubulointerstitial hypoxia in remnant kidney model plays a pathogenic role in the subsequent development of tubulointerstitial injury. The initial hypoxia in this model was dependent on activation of the renin-angiotensin system and hemodynamic alterations after nephron loss.

Original languageEnglish
Pages (from-to)1277-1288
Number of pages12
JournalJournal of the American Society of Nephrology
Volume15
Issue number5
DOIs
Publication statusPublished - 2004 May
Externally publishedYes

ASJC Scopus subject areas

  • Nephrology

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