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Inducible nitric oxide synthase inhibitor 1400W increases Na + ,K + ‐ ATP ase levels and activity and ameliorates mitochondrial dysfunction in Ctns null kidney proximal tubular epithelial cells
Author(s) -
Sumayao Rodolfo,
Newsholme Philip,
McMorrow Tara
Publication year - 2018
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12998
Subject(s) - nitric oxide synthase , nitric oxide , kidney , apoptosis , atp synthase , chemistry , acute kidney injury , medicine , nitrite , mitochondrion , endocrinology , microbiology and biotechnology , biochemistry , biology , enzyme , nitrate , organic chemistry
Summary Nitric oxide ( NO ) has been shown to play an important role in renal physiology and pathophysiology partly through its influence on various transport systems in the kidney proximal tubule. The role of NO in kidney dysfunction associated with lysosomal storage disorder, cystinosis, is largely unknown. In the present study, the effects of inducible nitric oxide synthase (iNOS)‐specific inhibitor, 1400W, on Na + ,K + ‐ ATP ase activity and expression, mitochondrial integrity and function, nutrient metabolism, and apoptosis were investigated in Ctns null proximal tubular epithelial cells ( PTEC s). Ctns null PTEC s exhibited an increase in iNOS expression, augmented NO and nitrite/nitrate production, and reduced Na + ,K + ‐ ATP ase expression and activity. In addition, these cells displayed depolarized mitochondria, reduced adenosine triphosphate content, altered nutrient metabolism, and elevated apoptosis. Treatment of Ctns null PTEC s with 1400W abolished these effects which culminated in the mitigation of apoptosis in these cells. These findings indicate that uncontrolled NO production may constitute the upstream event that leads to the molecular and biochemical alterations observed in Ctns null PTEC s and may explain, at least in part, the generalized proximal tubular dysfunction associated with cystinosis. Further studies are needed to realize the potential benefits of anti‐nitrosative therapies in improving renal function and/or attenuating renal injury in cystinosis.