Hypoxia-inducible factor (HIF) is a
transcription factor that regulates cellular hypoxic responses. Despite the therapeutic benefits of
cyclosporine A (CsA) in
organ transplantation, its clinical use is limited due to chronic nephropathy. We investigated whether HIF activation by
cobalt could improve CsA-induced nephropathy, and investigated the related mechanism. In animal experiments, rats were kept on a 0.05%
low-salt diet and administered CsA subcutaneously for 28 days (15 mg/kg/day). They also received
cobalt (10 mg/kg/day) during the entire experimental period. The administration of
cobalt significantly increased HIF-1α expression in the kidney. The increased expression of HIF-1α ameliorated CsA-induced afferent arteriolopathy and tubulointerstitial injury in the kidney.
Cobalt significantly reduced the infiltration of macrophages/monocytes into the renal tubulointerstitium. In addition, HIF activation by
cobalt reduced the number of CsA-induced apoptotic cells in the kidney. Subsequently, HK-2 human renal tubular epithelial cells were used for in vitro experiments. They were pre-treated with 150 µM of
cobalt to activate HIF, and then exposed to 10 µM CsA. HIF activation by
cobalt decreased the CsA-induced apoptosis in HK-2 cells, as judged by the decreases in the number of apoptotic cells, pro-apoptotic
caspase-3 activity, and the expression level of cleaved
caspase-3, together with the increase in the expression of anti-apoptotic bcl-2.
Cobalt pretreatment also reduced the CsA-induced phosphorylation of NF-κB and the CsA-induced expression of
vimentin and α-smooth muscle actin, suggesting the attenuation of
inflammation and
fibrosis. In conclusion, the activation of HIF by
cobalt may ameliorate the CsA-induced nephropathy by inhibiting apoptosis,
inflammation, and
fibrosis.