title: Time-dependent expression of renal vaso-regulatory molecules in LPS-induced endotoxemia in rat.
abstract: To elucidate roles of microvascular factors in the pathogenesis of renal complications during endotoxemia, that is characterized by renal vasoconstriction and systemic hypotension/generalized non-renal vasodilation, we profile the expression pattern and time-course of three key vaso-regulators, namely endothelin (ET)-1, nitric oxide (NO), and angiotensin II (Ang II). We hypothesize that disruption of the overall balance between vasodilatation and vasoconstriction in the kidney, during the early phase of sepsis, contribute to its (kidney) predisposition to acute renal failure. Adult male Wistar rats were rendered endotoxemic at different time points (1, 3, 6 and 10 h) by a single i.p. injection of lipopolysaccharide (LPS) (15 mg/kg) dissolved in saline. Control group was injected vehicle only (saline). Both systolic and diastolic blood pressures significantly decreased at different time points after LPS administration. Surprisingly, renal histopathological evaluation showed no remarkable changes in LPS-induced endotoxemia. However, overall, levels of the vaso-regulators and, where applicable, their respective receptors were upregulated: (1) plasma ET-1 increased 25-fold and peaked, as renal ET-1 mRNA, at 3 h; renal ET-1 protein and its receptors, ET type A (ET(A)) receptor (vasoconstrictive) and ET type B (ET(B)) receptor (vasodilatatory) increased in a time-dependent fashion, (2) Ang II increased by 53% compared to control, peaking at 6 h. However, while levels of Ang II type 1 (AT1) receptor increased over time after LPS injection, those of Ang II type 2 (AT2) receptor were downregulated, (3) data of NO system (NO-NOS), the key vasodilator, were the most intriguing. Whereas levels of renal NO increased time-dependently following LPS administration, with a 2240-fold increase in renal iNOS expression, levels of eNOS, were almost unchanged. In conclusion, the present study overall reveals intriguing and complex dynamics between levels of vasoconstrictors and vasodilators during the early phase of LPS-induced endotoxemia. These shifts in molecular expressions are likely triggered by compensatory mechanisms aimed at counteracting the undesirable and dominant effects of one group of vaso-regulatory moiety over the other.
authors.affiliation: Center for Medical Sciences, Ibaraki Prefectural University of Health Sciences, Ibaraki 300-0394, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Subrina
authors.initials: S
authors.lastname: Jesmin
authors.forename: Sohel
authors.initials: S
authors.lastname: Zaedi
authors.forename: Nobutake
authors.initials: N
authors.lastname: Shimojo
authors.forename: Seiji
authors.initials: S
authors.lastname: Maeda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Gando
authors.forename: Akio
authors.initials: A
authors.lastname: Koyama
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyauchi
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism*; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D017466:Receptors, Endothelin / Q000378:metabolism; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D044139:Receptor, Angiotensin, Type 2; D017466:Receptors, Endothelin; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; D007703:Peptidyl-Dipeptidase A