Renal tubular epithelial cell apoptosis is associated with caspase cleavage of the NHE1 Na+/H+exchanger

American Journal of Physiology - Renal Physiology - Tập 284 Số 4 - Trang F829-F839 - 2003
Karen Wu1,2, Shenaz Khan1,2, Sujata Lakhe-Reddy1,2, Liming Wang2, George Jarad1,2, R. Tyler Miller1,3, Martha Konieczkowski1,2, Arthur Brown1,4, John R. Sedor1,4,2, Jeffrey R. Schelling1,2
1Departments of Medicine, and
2Rammelkamp Center for Education and Research, Case Western Reserve University School of Medicine, Cleveland 44109; and
3Louis B. Stokes Veterans Administration Medical Center, Cleveland, Ohio 44106
4§Physiology and Biophysics, and

Tóm tắt

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 Na+/H+exchanger (NHE) 1. We investigated whether RTC apoptosis requires caspase cleavage of NHE1. Staurosporine- and hypertonic NaCl-induced RTC apoptosis was associated with cell shrinkage and diminished cytosolic pH, and apoptosis was potentiated by amiloride analogs, 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 molecular weight to NHE1 degradation products derived from staurosporine-stimulated RTC lysates. In vivo, NHE1 loss-of-function C57BL/6.SJL- swe/swemice with adriamycin-induced nephropathy demonstrated increased RTC apoptosis compared with 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 that caspase cleavage of RTC NHE1 may promote apoptosis and tubular atrophy by preventing compensatory intracellular volume and pH regulation.

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American Journal of Physiology - Renal Physiology

Tập 284 Số 4

F829-F839

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