Luminal alkalinization attenuates proteinuria-induced oxidative damage in proximal tubular cells.

Abstract

A highly acidic environment surrounds proximal tubular cells as a result of their reabsorption of HCO(3)(-). It is unclear whether this luminal acidity affects proteinuria-induced progression of tubular cell damage. Here, we investigated the contribution of luminal acidity to superoxide (O(2)(·-)) production induced by oleic acid-bound albumin (OA-Alb) in proximal tubular cells. Acidic media significantly enhanced OA-Alb-induced O(2)(·-) production in the HK-2 proximal tubular cell line. Simultaneous treatment with both OA-Alb and acidic media led to phosphorylation of the intracellular pH sensor Pyk2. Highly phosphorylated Pyk2 associated with activation of Rac1, an essential subcomponent of NAD(P)H oxidase. Furthermore, knockdown of Pyk2 with siRNA attenuated the O(2)(·-) production induced by cotreatment with OA-Alb and acid. To assess whether luminal alkalinization abrogates proteinuria-induced tubular damage, we studied a mouse model of protein-overload nephropathy. NaHCO(3) feeding selectively alkalinized the urine and dramatically attenuated the accumulation of O(2)(·-)-induced DNA damage and proximal tubular injury. Overall, these observations suggest that luminal acidity aggravates proteinuria-induced tubular damage and that modulation of this acidic environment may hold potential as a therapeutic target for proteinuric kidney disease.

• Authors: Tomokazu Souma, Michiaki Abe, Takashi Moriguchi, Jun Takai, Noriko Yanagisawa-Miyazawa, Eisuke Shibata, Yasutoshi Akiyama, Takafumi Toyohara, Takehiro Suzuki, Masayuki Tanemoto, Takaaki Abe, Hiroshi Sato, Masayuki Yamamoto, Sadayoshi Ito
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 22 Issue 4 Pg. 635-48 (Apr 2011) ISSN: 1533-3450 [Electronic] United States
• PMID: 21372211 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 by the American Society of Nephrology

Chemical References

• Albumins
• Reactive Oxygen Species
• Oleic Acid
• Sodium Bicarbonate
• NADPH Oxidases
• Focal Adhesion Kinase 2
• Oxygen

Topics

• Albumins (pharmacology)
• Animals
• Apoptosis (drug effects)
• Cell Line
• DNA Damage (drug effects)
• Disease Models, Animal
• Disease Progression
• Female
• Focal Adhesion Kinase 2 (metabolism)
• Humans
• Hydrogen-Ion Concentration
• Kidney Diseases (etiology, metabolism, physiopathology)
• Kidney Tubules, Proximal (drug effects, pathology, physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• NADPH Oxidases (metabolism)
• Oleic Acid (pharmacology)
• Oxidative Stress (drug effects, physiology)
• Oxygen (metabolism)
• Proteinuria (complications, metabolism, prevention & control)
• Reactive Oxygen Species (metabolism)
• Sodium Bicarbonate (pharmacology, therapeutic use)