Inducible nitric oxide synthase-derived nitric oxide promotes mitochondrial dysfunction, altered nutrient metabolism, and apoptosis in Ctns null kidney proximal tubular epithelial cells

College

College of Science

Department/Unit

Chemistry

Document Type

Article

Source Title

Free Radical Biology and Medicine

Volume

128

Issue

Supplement 1

First Page

S94

Publication Date

11-2018

Abstract

Nitric oxide (NO) has been shown to play an important role in renal physiology and pathophysiology partly through its influence on various solute transport systems in the kidney proximal tubule. Coincidentally, the same transport systems are affected in the lysosomal storage disorder, cystinosis, which manifest clinically as renal Fanconi syndrome. Cystinosis is caused by one or more mutations in the CTNS gene, which codes for a lysosomal transmembrane protein, cystinosin. Several in vitro and in vivo studies have implicated oxidative stress in the pathogenesis of cystinosis. However, the role of NO in the kidney dysfunction associated with cystinosis is largely unknown. In the present study, the effects of NO on Na+,K+-ATPase activity and expression, mitochondrial integrity and function, nutrient metabolism, and apoptosis were investigated in Ctns null proximal tubular epithelial cells (PTECs). Ctns null PTECs exhibited an increase in inducible nitric oxide synthase (iNOS) expression which resulted in the augmentation of intracellular NO levels and extracellular nitrite/nitrate production. This was accompanied by a reduction in Na+,K+-ATPase expression and activity. In addition, Ctns null PTECs displayed depolarized mitochondria, reduced ATP production, altered nutrient metabolism, and elevated apoptosis. Treatment of Ctns null PTECs with an iNOS-selective inhibitor, 1400W, abolished these effects which culminated in the mitigation of apoptosis. These findings indicate that excessive NO production by iNOS may constitute an upstream event that leads to the molecular and biochemical alterations observed in Ctns null PTECs. This may explain, at least in part, the generalized kidney proximal tubular dysfunction associated with cystinosis. Further studies are needed to realize the potential benefits anti-nitrosative therapies in improving renal function and/or attenuating renal injury in cystinosis.

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Disciplines

Chemistry

Keywords

Nitric oxide; Nitric-oxide synthase; Cystinosis

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