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1
1 in the Regulation of Renal Medullary Osmolyte Concentration
1 Renal Pathology Division, Department of Pathology and the Nephrology Division, Department of Medicine, Vanderbilt School of Medicine, Nashville, TN, USA
2 Nephrology Division, Department of Medicine, Veterans Affairs Hospital and Vanderbilt School of Medicine, Nashville, TN, USA
* To whom correspondence should be addressed. E-mail: gilbert.moeckel{at}vanderbilt.edu.
The mechanism by which cells sense extracellular tonicity and trigger the
accumulation of protective organic osmolytes is poorly understood. It has been proposed
that changes in cell volume following alteration of extracellular toncity are important
initiators of signaling events that lead to osmolyte accumulation. Since the extracellular
matrix receptors integrins are linked to the cytoskeleton and can transduce signals that
alter cell behavior, we investigate the role of these receptors in the modulation of
osmolyte accumulation in the kidney medulla under different osmotic conditions. We
show that integrin 
1-null mice have impaired ability to accumulate organic osmolytes in
the inner medulla due to altered signaling and decreased induction of osmolyte
transporters or aldose reductase gene transcription. Utilizing inner medullary collecting
duct cells we demonstrate that the lack of integrin 1
1 results in an impaired ability to
induce the tonicity enhancer binding protein TonEBP under hypertonic conditions.
Furthermore, under the same conditions, integrin 1-null cells show prolonged ERK1/2
phosphorylation and decreased inositol uptake compared to control cells. The reduction
of inositol uptake is significantly reversed by treatment with the MEK inhibitor
PD98059. Finally, integrin 1-null mice develop morphologic changes of early tubular
necrosis and increased apoptosis of renal medullary cells following dehydration.
Together these results show that integrin 11 is an important mediator of the compatible
osmolyte response in the medulla of the mammalian kidney.
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