Intracellular acidification mediates the inhibitory effect of peritoneal dialysate on peritoneal macrophages

A. Douvdevani, J. Rapoport, A. Konforty, R. Yulzari, A. Moran, C. Chaimovitz

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Commercial peritoneal dialysis solution (CDS) is known to have a detrimental effect on the capacity of peritoneal macrophages (PMΦ) to kill bacteria and produce acute phase cytokines. This cytotoxic effect is largely caused by the low pH of CDS. Because the cytoplasmic pH (pHi) is an important determinant of cellular function, the effect of CDS on the pHi of PMΦ from continuous ambulatory peritoneal dialysis patients was studied. The pHi of PMΦ was measured fluorometrically in N-hydroxyethylpiperazine-N'-2-ethanesulFonic acid (HEPES)-buffered salt solution (HBSS) or CDS at pH values of 5.3, 6.5, and 7.0 values that represent the pH existing in dialysate during the first 30 min of dwell time. For any given pH of the experimental medium, the pHi was always more acidic in CDS than in HBSS. When PMΦ were incubated with a lactate-containing HBSS, a cellular acidification was observed that was similar to that attained by exposure to CDS at the same pH. This supports the hypothesis that the decrease in pHi was due to the influx of lactic acid from the CDS into the PMΦ. In order to demonstrate a causal association between the CDS-induced cellular acidification and a defect in phagocytosis and cytokine production, these functions were studied after pHi clamping by means of K+/nigericin. it was found that clamping pHi to values below 6.5 led to a markedly reduced tumor necrosis factor-α production and phagocytosis. However, at values of pHi >6.5, these functions were normal. The acid loading of PMΦ with CDS was followed by a partial recovery of pHi toward the resting pHi. This recovery reflects the activity of the Na+/H+ exchanger, as evidenced by its sensitivity to amiloride and an H+-ATPase sensitive to N,N-dicyclohexylcarbodiimide. It was concluded that: (1) exposure of PMΦ to CDS causes a profound drop in pHi due to the cellular accumulation of lactic acid. (2) The CDS-mediated PMΦ acidosis probably plays a major role in the known inhibitory effect of CDS on phagocytosis and cytokine production. (3) The partial recovery of pHi observed after the exposure of the cells to CDS of pH 6.5 and 7.0 was mediated by an Na+/H+ antiporter and a proton ATPase.

Original languageEnglish
Pages (from-to)207-213
Number of pages7
JournalJournal of the American Society of Nephrology : JASN
Volume6
Issue number2
StatePublished - 1 Jan 1995
Externally publishedYes

Keywords

  • Acidifcation
  • Continuous ambulatory peritoneal dialysis
  • Macrophages
  • Tumor necrosis factor-α

Fingerprint

Dive into the research topics of 'Intracellular acidification mediates the inhibitory effect of peritoneal dialysate on peritoneal macrophages'. Together they form a unique fingerprint.

Cite this