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Luminal alkalinization attenuates proteinuria-induced oxidative damage in proximal tubular cells.
- Source :
-
Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2011 Apr; Vol. 22 (4), pp. 635-48. Date of Electronic Publication: 2011 Mar 03. - Publication Year :
- 2011
-
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.<br /> (Copyright © 2011 by the American Society of Nephrology)
- Subjects :
- 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 metabolism
Kidney Tubules, Proximal drug effects
Kidney Tubules, Proximal pathology
Male
Mice
Mice, Inbred C57BL
NADPH Oxidases metabolism
Oleic Acid pharmacology
Oxidative Stress drug effects
Oxygen metabolism
Proteinuria metabolism
Reactive Oxygen Species metabolism
Sodium Bicarbonate pharmacology
Kidney Diseases etiology
Kidney Diseases physiopathology
Kidney Tubules, Proximal physiopathology
Oxidative Stress physiology
Proteinuria complications
Proteinuria prevention & control
Sodium Bicarbonate therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1533-3450
- Volume :
- 22
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of the American Society of Nephrology : JASN
- Publication Type :
- Academic Journal
- Accession number :
- 21372211
- Full Text :
- https://doi.org/10.1681/ASN.2009111130