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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Souma, T; Abe, M; Moriguchi, T; Takai, J; Yanagisawa-Miyazawa, N; Shibata, E; Akiyama, Y; Toyohara, T; Suzuki, T; Tanemoto, M; Abe, T; Sato, H; Yamamoto, M; Ito, S

Published Date

  • April 2011

Published In

Volume / Issue

  • 22 / 4

Start / End Page

  • 635 - 648

PubMed ID

  • 21372211

Pubmed Central ID

  • 21372211

Electronic International Standard Serial Number (EISSN)

  • 1533-3450

International Standard Serial Number (ISSN)

  • 1046-6673

Digital Object Identifier (DOI)

  • 10.1681/ASN.2009111130

Language

  • eng