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Abstract: PO1418

Oxidized Alkyl Phospholipids Stimulate Proximal Tubule Sodium Transport via PPARγ/ERK Pathway

Session Information

Category: Fluid, Electrolyte, and Acid-Base Disorders

  • 901 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

  • Mizuno, Tomohito, Division of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
  • Nakamura, Motonobu, Division of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
  • Satoh, Nobuhiko, Division of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
  • Tsukada, Hiroyuki, Division of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
  • Sato, Yusuke, Department of Urology, The University of Tokyo, Tokyo, Japan
  • Horita, Shoko, Division of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
  • Kume, Haruki, Department of Urology, The University of Tokyo, Tokyo, Japan
  • Suzuki, Masashi, Tokyo Yamate Medical Center, Tokyo, Japan
  • Nangaku, Masaomi, Division of Nephrology and Endocrinology, The University of Tokyo, Tokyo, Japan
Background

We previously reported thiazolidinediones stimulated proximal tubule (PT) sodium transport via non-genomic PPARγ/ERK pathway. However, the contribution of endogenous PPARγ ligands to PT transport has been unknown. In this study, we investigated effects of 1-O-hexadecyl-2-azelaoyl-sn-glycero-3-phosphocholine (azPC), an endogenous lipid oxidation product (LOP) acting as a potent PPARγ agonist, on PT sodium transport.

Methods

We measured basolateral Na+/HCO3- cotransporter 1 (NBCe1) activity in lumen-collapsed PTs and luminal Na+/H+ exchanger (NHE) activity in freshly-isolated rat and human PTs obtained during surgery for renal cell carcinoma by using a pH-sensitive dye BCECF. NBCe1 activity in lumen-collapsed PTs was measured by the rate of pHi decrease in response to HCO3- reduction. Luminal NHE activity in lumen-opened PTs was measured by the rate of pHi decrease caused by Na+ removal in the presence of VATPase inhibitor, Bafilomycin A1. To examine the signaling pathway of azPC, we used a PPARγ antagonist (GW9662) and a MEK inhibitor (PD98059) and siRNA against PPARγ. The expression of PPARγ mRNA was determined by quantitative PCR. ERK phosphorylation was analyzed by western blotting.

Results

In freshly-isolated human and rat PTs, 0.3 µM azPC stimulated NBCe1 and NHE activity. The stimulatory effects were completely suppressed by GW9662 or PD98059 without affecting the basal activities. siRNA against PPARγ completely suppressed the stimulation of both NBCe1 and NHE activities by azPC in rat PTs. We found that azPC enhanced ERK phosphorylation in human and rat renal cortex tissue. This phosphorylation was also completely suppressed by GW9662 or PD98059.

Conclusion

These results indicated azPC stimulated both NBCe1 and NHE activities through PPARγ/ERK pathway in PTs. The stimulatory effect of azPC, one of the LOPs on PT sodium reabsorption, could be a novel mechanism of volume expansion and hypertension induced by atherosclerosis.