Inducible nitric oxide synthase inhibitor 1400W increases Na+ ,K+ -ATPase levels and activity and ameliorates mitochondrial dysfunction in Ctns null kidney proximal tubular epithelial cells.

Abstract

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+ -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 iNOS expression, augmented NO and nitrite/nitrate production, and reduced Na+ ,K+ -ATPase expression and activity. In addition, these cells displayed depolarized mitochondria, reduced adenosine triphosphate content, altered nutrient metabolism, and elevated apoptosis. Treatment of Ctns null PTECs 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 PTECs 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.

• Authors: Rodolfo Sumayao Jr, Philip Newsholme, Tara McMorrow
• Journal: Clinical and experimental pharmacology & physiology (Clin Exp Pharmacol Physiol) Vol. 45 Issue 11 Pg. 1149-1160 (11 2018) ISSN: 1440-1681 [Electronic] Australia
• PMID: 29924417 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 John Wiley & Sons Australia, Ltd.

Chemical References

• Amidines
• Amino Acid Transport Systems, Neutral
• Benzylamines
• Enzyme Inhibitors
• N-(3-(aminomethyl)benzyl)acetamidine
• cystinosin protein, mouse
• Nitric Oxide
• Nitric Oxide Synthase Type II
• Sodium-Potassium-Exchanging ATPase

Topics

• Amidines (pharmacology)
• Amino Acid Transport Systems, Neutral (deficiency, genetics)
• Animals
• Apoptosis (drug effects)
• Benzylamines (pharmacology)
• Cell Line
• Cell Survival (drug effects)
• Enzyme Inhibitors (pharmacology)
• Epithelial Cells (cytology, drug effects, metabolism)
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Knockout Techniques
• Kidney Tubules, Proximal (cytology)
• Mice
• Mitochondria (drug effects, pathology)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (antagonists & inhibitors)
• Nutrients (metabolism)
• Oxidative Stress (drug effects)
• Sodium-Potassium-Exchanging ATPase (metabolism)