Modulation of ureteric Ca signaling and contractility in humans and rats by uropathogenic E. coli.
Ascending urinary tract infections, a significant cause of kidney damage, are predominantly caused by uropathogenic Escherichia coli (UPEC). However, the role and mechanism of changes in ureteric function during infection are poorly understood. We therefore investigated the effects of UPEC on Ca signaling and contractions in rat (n = 17) and human (n = 6) ureters. Ca transients and force were measured and effects of UPEC on the urothelium were monitored in live tissues. In both species, luminal exposure of ureters to UPEC strains J96 and 536 caused significant time-dependent decreases in phasic and high K depolarization-induced contractility, associated with decreases in the amplitude and duration of the Ca transients. These changes were significant after 3-5 h and irreversible over the next 5 h. The infection causes increased activity of K channels, causing inhibition of voltage-gated Ca entry, and K channel blockers could reverse the effects of UPEC on ureteric function. A smaller direct effect on Ca entry also occurs. Nonpathogenic E. coli (TG2) or abluminal application of UPEC did not produce changes in Ca signaling or contractility. UPEC exposure also caused significant impairment of urothelial barrier function; luminal application of the Ca channel blocker nifedipine caused a reduction in contractions as it entered the tissue, an effect not observed in untreated ureters. Thus, UPEC impairs ureteric contractility in a Ca-dependent manner, largely caused by stimulation of potassium channels and this mechanism is dependent on host-urothelium interaction.
Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Liverpool, UK. floyd78@liv.ac.uk
Rachel V
RV
Floyd
Craig
C
Winstanley
Ali
A
Bakran
Susan
S
Wray
Theodor V
TV
Burdyga
D000328:Adult; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D004927:Escherichia coli Infections / Q000378:metabolism* / Q000382:microbiology / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D051381:Rats; D014513:Ureter / Q000166:cytology / Q000502:physiology*; D056689:Uropathogenic Escherichia coli / Q000502:physiology*