Role of integrin 1 1 in the regulation of renal medullary osmolyte concentration

Moeckel, Gilbert W., Li Zhang, Xiwu Chen, Michele Rossini, Roy Zent, and Ambra Pozzi. Role of integrin 1 1 in the regulation of renal medullary osmolyte concentration. Am J Physiol Renal Physiol 290: F223–F231, 2006. First published August 16, 2005; doi:10.1152/ajprenal.00371.2004.—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. Because the extracellular matrix receptors integrins are linked to the cytoskeleton and can transduce signals that alter cell behavior, we investigated 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 with control cells. The reduction of inositol uptake is significantly reversed by treatment with the MEK inhibitor PD-98059. Finally, integrin 1-null mice develop morphological changes of early tubular necrosis and increased apoptosis of renal medullary cells following dehydration. Together, these results show that integrin 1 1 is an important mediator of the compatible osmolyte response in the medulla of the mammalian kidney.