N. Kumagai et al., Mitogenic action of lysophosphatidic acid in proximal tubular epithelial cells obtained from voided human urine, CLIN SCI, 99(6), 2000, pp. 561-567
Focal tubular cell multiplication at sites on an injured nephron is a criti
cal event in the recovery phase following acute tubular necrosis. During th
is process, numerous viable tubular cells exfoliate and are shed into the u
rine. Lysophosphatidic acid (LPA) is generated in the plasma membrane of in
jured cells and acts as an intercellular mediator of various biological pro
cesses, including inflammation, proliferation and repair. In the present st
udy, exfoliated proximal tubule (PT) cells were isolated from human urine a
nd the mitogenic effects of LPA were investigated as a model of repair and
proliferation following renal injury. LPA stimulated a 23.5% increase in DN
A synthesis, a 29.4% increase in cell number and an 86.6% decrease in cAMP
content. All of these responses were pertussis toxin sensitive, indicating
the involvement of G(i)-type G-proteins in LPA signalling. Conversely, the
LPA-induced DNA synthesis and the decrease in intracellular cAMP content we
re insensitive to wortmannin, an inhibitor of phosphatidylinositol 3-kinase
(PI3K), suggesting a mitogenic response via PI3K-independent mechanisms. F
urthermore, we detected specific mRNA transcripts for the recently cloned h
uman LPA-receptors, endothelial differentiation gene (Edg)-2 and Edg-4 (Edg
-2 much greater than Edg-4) by reverse transcription-PCR in PT cells. Our d
ata suggest that LPA may behave as a local growth factor in PT cells follow
ing tubular injury.