title: Indomethacin blocks enhanced paracellular backflux in proximal tubules.
abstract: Renal interstitial hydrostatic pressure (RIHP) is a link between increased arterial BP and natriuresis. The mechanism whereby increases in RIHP inhibits sodium and water transport across the mammalian proximal tubule epithelium may involve changes in flux across the tight junction of the proximal tubule. The purpose of this study was to determine the effects of increases in RIHP and inhibition of cyclooxygenase on paracellular backflux of an extracellular marker from the renal interstitium into the proximal tubule of the rat. During in vivo microperfusion of proximal tubules, the extracellular tracer of paracellular flux, lanthanum (La), was infused directly into the renal interstitium via a chronically implanted matrix. The net paracellular interstitium-to-lumen lanthanum backflux was measured before and after direct renal interstitial volume expansion (DRIVE) in the absence and presence of indomethacin. DRIVE significantly increased RIHP by 37% (Delta1.8 +/- 0.2 mmHg) and interstitium-to-lumen La backflux by 32% (Delta40.2 +/- 16.6 pg/min per mm), and it significantly decreased proximal reabsorption by 27% (Delta-7.7 +/- 3.8 nl/min; n = 6). In indomethacin-treated rats (n = 6), DRIVE again significantly increased RIHP by 40% (Delta1.9 +/- 0.2 mmHg), but it did not increase La backflux (Delta-39.0 +/- 24.4 pg/min per mm) or significantly decrease proximal reabsorption (Delta1.2 +/- 2.3 nl/min). These results demonstrate that increased RIHP increases paracellular backflux of lanthanum from the renal interstitium to the proximal tubule lumen in association with decreases in proximal reabsorption. Furthermore, indomethacin blocks the effects of increased RIHP on proximal reabsorption and paracellular backflux of lanthanum through the intercellular tight junctions of the proximal tubule epithelium.
authors.affiliation: Department of Internal Medicine and Physiology and Biophysics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.
authors.forename: Carla R
authors.initials: CR
authors.lastname: Ramsey
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: Berndt
authors.forename: Franklyn G
authors.initials: FG
authors.lastname: Knox
mesh_terms: D000042:Absorption; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006874:Hydrostatic Pressure; D007213:Indomethacin / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D007811:Lanthanum / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D007811:Lanthanum; D007213:Indomethacin