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Articles in PresS, published online ahead of print November 26, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00314.2002
Submitted on September 3, 2002
Accepted on November 18, 2002
1 Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Department of Physiology and Biophysics, Rammelkamp Center for Education and Research, CWRU MetroHealth Medical Center Campus, Cleveland, Ohio, USA
2 Department of Physiology and Biophysics, Rammelkamp Center for Education and Research, CWRU MetroHealth Medical Center Campus, Cleveland, Ohio, USA
3 Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA; Department of Medicine, Louis B. Stokes Veterans Administration Medical Center, Cleveland, Ohio, USA
* To whom correspondence should be addressed. E-mail: jrs15{at}po.cwru.edu.
Renal tubular epithelial cell (RTC) apoptosis causes tubular atrophy, a hallmark of renal disease progression. Apoptosis is generally characterized by reduced cell volume and cytosolic pH, but epithelial cells are relatively resistant to shrinkage, due to regulatory volume increase, which is mediated by NHE1. We investigated whether RTC apoptosis requires caspase cleavage of NHE1. Staurosporine- and hypertonic NaCl-induced RTC apoptosis were associated with cell shrinkage and diminished cytosolic pH, and apoptosis was potentiated by amiloride analogues, suggesting NHE1 activity opposes apoptosis. NHE1-deficient fibroblasts demonstrated increased susceptibility to apoptosis, which was reversed by NHE1 reconstitution. NHE1 expression was markedly decreased in apoptotic RTC due to degradation, and preincubation with peptide caspase antagonists restored NHE1 expression, indicating that NHE1 is degraded by caspases. Recombinant caspase-3 cleaved the in vitro-translated NHE1 cytoplasmic domain into five distinct peptides, identical in Mr to NHE1 degradation products derived from staurosporine-stimulated RTC lysates. In vivo, NHE1 loss-of-function C57BL/6.SJL-swe/swe mice with adriamycin-induced nephropathy demonstrated increased RTC apoptosis compared to adriamycin-treated wild-type controls, thereby implicating NHE1 inactivation as a potential mechanism of tubular atrophy. We conclude that NHE1 activity is critical for RTC survival after injury and caspase cleavage of RTC NHE1 may promote apoptosis and tubular atrophy by preventing compensatory intracellular volume6 and pH regulation.
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