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Am J Physiol Regul Integr Comp Physiol (May 11, 2006). doi:10.1152/ajpregu.00152.2006
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Submitted on March 6, 2006
Accepted on May 8, 2006

Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal and muscular degeneration

Katja Heinicke1, Oliver Baum2, Omolara O Ogunshola1, Johannes Vogel1, Thomas Stallmach3, David P Wolfer4, Stephan Keller1, Klaus Weber5, Peter D. Wagner6, Max Gassmann1, and Valentin Djonov2*

1 Vetsuisse Faculty and Zurich Center for Integrative Human Physiology (ZIHP), Institute of Veterinary Physiology, Zurich, Switzerland
2 University of Berne, Institute of Anatomy, Berne, Switzerland
3 University of Zurich, Institute of Pathology, Zurich, Switzerland
4 University of Zurich, Institute of Anatomy, Switzerland
5 RCC, Itingen, Switzerland
6 Department of Medicine, University of California San Diego, Division of Physiology, La Jolla, California, United States

* To whom correspondence should be addressed. E-mail: valentin.djonov{at}ana.unibe.ch.

To investigate the consequences of inborn excessive erythrocytosis we made use of our transgenic mouse line (tg6) that constitutively overexpresses erythropoietin (Epo) in a hypoxia-independent manner, thereby reaching hematocrit levels of up to 0.89. We detected expression of human Epo in the brain and, to a lesser extent, in the lung but not in the heart, kidney or liver of tg6 mice. Although no acute cardiovascular complications are observed, tg6 animals have a reduced lifespan. Decreased swim performance was observed in five month old tg6 mice. At about seven months, several tg6 animals developed spastic contractions of the hind limbs followed by paralysis. Morphological analysis by light and electron microscopy showed degenerative processes in liver and kidney characterized by increased vascular permeability, chronic progressive inflammation, hemosiderin deposition and general vasodilatation. Moreover, most of the animals showed severe nerve fiber degeneration of the sciatic nerve, decreased number of neuromuscular junctions and degeneration of skeletal muscle fibers. Most probably, the developing demyelinating neuropathy resulted in muscular degeneration demonstrated in the extensor digitorum longus muscle. Taken together, chronically increased Epo levels inducing excessive erythrocytosis leads to multiple organ degeneration and reduced life expectancy. This model allows investigation of the impact of excessive erythrocytosis in individuals suffering from polycythemia vera, chronic mountain sickness or in subjects tempted to abuse Epo by means of gene doping.




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