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-1␣, 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-1␣ 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.

Hypoxia can induce tubular EMT. This process may play an important role in progression of kidney disease.

Our studies demonstrated a crucial role of HIF in the renal medulla under normal and hypoxic circumstances.

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Previous in vitro studies indicated that aldosterone nongenomically phosphorylates epidermal growth factor receptor (EGFR) through activation of upstream signals, heat shock protein 90β (Hsp90β), and cytosolic (c)-Src kinase. We demonstrated that aldosterone rapidly elevates EGFR phosphorylation in rat kidney. There are no in vivo data regarding renal Hsp90(α and β) and phosphorylated (p)c-Src protein expressions. The present study further investigates the expressions of these proteins. Male Wistar rats were intraperitoneally injected with normal saline solution or aldosterone (Aldo: 150 μg/kg BW). After 30 minutes, abundances and localizations of these proteins were determined. Aldosterone enhanced renal Hsp90β protein abundance (P < 0.001), but Hsp90α and pc-Src protein levels remained unaltered. Expression of Hsp90(α and β) was induced prominently in the proximal convoluted tubules (PCTs). Activation of Hsp90α was observed in vascular and outer medulla regions, whereas Hsp90β was induced in the cortex. Immunoreactivity of pc-Src was elevated in PCT with obvious staining at the luminal membrane. This in vivo study is the first to demonstrate that aldosterone nongenomically elevates Hsp90(α and β) protein expressions in rat kidney. Aldosterone had no effect on pc-Src protein levels but modulated localization. These results indicate that aldosterone regulates upstream mediators of EGFR transactivation in vivo.