4.6 Article

Stabilization of hypoxia-inducible factor 1α by cobalt chloride impairs podocyte morphology and slit-diaphragm function

Journal

JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 120, Issue 5, Pages 7667-7678

Publisher

WILEY
DOI: 10.1002/jcb.28041

Keywords

cobalt chloride; hypoxia-inducible factor 1 alpha; podocytes; proteinuria; slit-diaphragm

Funding

  1. Science and Engineering Research Board [2015/2076]
  2. Defence Research and Development Organisation [LSRB-296]

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Glomerular podocytes are the major components of the renal filtration barrier, and altered podocyte permselectivity is a key event in the pathogenesis of proteinuric conditions. Clinical conditions such as ischemia and sleep apnea and extreme physiological conditions such as high-altitude sickness are presented with renal hypoxia and are associated with significant proteinuria. Hypoxia is considered as an etiological factor in the progression of acute renal injury. A sustained increase in hypoxia-inducible factor 1 alpha (HIF1 alpha) is a major adaptive stimulus to the hypoxic conditions. Although the temporal association between hypoxia and proteinuria is known, the mechanism by which hypoxia elicits proteinuria remains to be investigated. Furthermore, stabilization of HIF1 alpha is being considered as a therapeutic option to treat anemia in patients with chronic kidney disease. Therefore, in this study, we induced stabilization of HIF1 alpha in glomerular regions in vivo and in podocytes in vitro upon exposure to cobalt chloride. The elevated HIF1 alpha expression is concurrence with diminished expression of nephrin and podocin, podocyte foot-processes effacement, and significant proteinuria. Podocytes exposed to cobalt chloride lost their arborized morphology and cell-cell connections and also displayed cytoskeletal derangements. Elevation in expression of HIF1 alpha is in concomitance with loss of nephrin and podocin in patients with diabetic nephropathy and chronic kidney disease. In summary, the current study suggests that HIF1 alpha stabilization impairs podocyte function vis-a-vis glomerular permselectivity.

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