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

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

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

A highly acidic environment surrounds proximal tubular cells as a result of their reabsorption of HCO3-. 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 O2·- 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. NaHCO3 feeding selectively alkalinized the urine and dramatically attenuated the accumulation of O2·--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.

Original languageEnglish
Pages (from-to)635-648
Number of pages14
JournalJournal of the American Society of Nephrology
Volume22
Issue number4
DOIs
Publication statusPublished - 2011 Apr

ASJC Scopus subject areas

  • Nephrology

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