Effects of lipid A on calcium homeostasis in renal proximal tubules.
It is clear that lipopolysaccharides (LPS) are responsible for the multiorgan failure often associated with endotoxemia. However, little is known of the direct effects of LPS on kidney cells. We examined the effects of lipid A, the biologically active component of LPS, on rat proximal tubule Ca++ homeostasis. Lipid A produced a rapid, transient, concentration-dependent rise in intracellular Ca++ concentration, [Ca++]i, as monitored by fura-2. At 50 micrograms/ml [Ca++]i rose to 138 +/- 12 nM (n = 4) above basal [Ca++]i levels. The response to lipid A was not significantly inhibited by chelating extracellular Ca++ with EGTA (5 mM). However, the rise in [Ca++]i was significantly inhibited by 8-(N,N-dimethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride) and thapsigargin (17 +/- 7 nM and 13 +/- 9 nM rise, respectively; P < .05). These data indicate that the rise in [Ca++]i induced by lipid A is due to release of intracellular stores, and not extracellular influx. We also examined the role of inositol 1,4,5-trisphosphate in the lipid A response. Lipid A caused a time-dependent increase in inositol 1,4,5-trisphosphate that paralleled the rise in [Ca++]i, suggesting the release in [Ca++]i is through an inositol 1,4,5-trisphosphate-mediated release of intracellular stores. The ability of lipid A to alter Ca++ homeostasis suggests a potential for LPS to directly alter proximal tubule physiology and renal function in vivo.
Proksch
J W
JW
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, USA.
Traylor
L A
LA
Mayeux
P R
PR
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004533:Egtazic Acid / Q000494:pharmacology; D005707:Gallic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects*; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D008050:Lipid A / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D008050:Lipid A; D004533:Egtazic Acid; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D005707:Gallic Acid; D002118:Calcium