Cobalt promotes angiogenesis via hypoxia-inducible factor and protects tubulointerstitium in the remnant kidney model

Abstract

Tubulointerstitial hypoxia has been implicated in a number of progressive renal diseases, and several lines of evidence indicate that the administration of angiogenic growth factors ameliorates tubulointerstitial injury. We hypothesized that induction of hypoxia-inducible factors (HIF) mediates renoprotection by their angiogenic properties. At 5-9 weeks after subtotal nephrectomy, cobalt was administered to rats to activate HIF. Histological evaluation demonstrated that the tubulointerstitial injury was significantly ameliorated in animals that received cobalt (score: 2.5170.12 (cobalt) vs 3.2170.24 (vehicle), Po0.05). Furthermore, animals receiving cobalt had fewer vimentin-and TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells. The renoprotective effect of cobalt was associated with the preservation of peritubular capillary networks (rarefaction index: 13.770.4 (cobalt) vs 18.670.9 (vehicle), Po0.01). This improvement in capillary networks was accompanied by an increased number of proliferating (PCNA-positive) glomerular and peritubular endothelial cells. The angiogenesis produced by this method was not accompanied by an increase in vascular permeability. Furthermore, in vitro experiments clarified that HIF-1 in tubular epithelial cells promotes proliferation of endothelial cells and that HIF-2 overexpressed in renal endothelial cells mediates migration and network formation. Collectively, these findings demonstrate a renoprotective role of HIF through angiogenesis and provide a rationale for therapeutic approaches to target HIF for activation.

Activation of the Renin-Angiotensin System and Chronic Hypoxia of the Kidney

“…Previous studies by our group and others have demonstrated that stimulation of HIF with cobalt chloride is effective in a variety of kidney disease models (73)(74)(75)(76)(77). Furthermore, pretreatment with either carbon monoxide, leading to tissue hypoxia, or the novel prolyl hydroxylase inhibitor FG-4487 strongly induced the accumulation of HIF-1α and HIF-2α in tubular and peritubular cells, respectively, with significant amelioration of ischemic renal injury (78).…”

Chronic Hypoxia and Tubulointerstitial Injury

“…Administration induced upregulation of HIF-regulated genes, such as VEGF and EPO, and subsequently protected the kidney against the tubulointerstitial damage induced by hypoxia. Cobalt treatment was also effective when given after the initial insult in a chronic progressive glomerulonephritis model, a model of cyclosporin nephrotoxicity, and a model of chronic renal failure with glomerular hypertension, demonstrating not only its preventive but also its therapeutic potential (70,74,75).…”

“…Although cell-type specificity of HIF isoforms in these models was consistent with previous findings, temporal and spatial profiles of HIF activation were relatively complex, suggesting an important but complicated role of HIF in tissue preservation as a response to regional renal hypoxia. Our recent in vitro experiments showed that HIF-1 in tubular epithelial cells promotes proliferation of endothelial cells and that HIF-2 that is overexpressed in renal endothelial cells mediates migration and network formation; these results suggest a specific role of each isoform in certain cell types (70), although a clear differentiation of their roles independent of localization remains controversial.…”

Hypoxia and the HIF system in kidney disease

“…We also treated rats with the remnant kidney model, classically characterized by chronic renal failure with glomerular sclerosis and hypertension. Cobalt treatment mediated improvement in the tubulointerstitial injury as well as preservation of glomerular and peritubular capillary networks with no evidence of vascular leakage [45]. On the other hand, activation of the HIF system in podocytes induced by VHL knockout was recently reported to result activation and proliferation of podocytes and resulted in a pathology resembling rapid progressive glomerulonephritis [46].…”