TGF-Beta1 Release by Volatile Anesthetics Mediates Protection against Renal Proximal Tubule Cell Necrosis

Abstract

Background/Aims:We have previously demonstrated that clinically utilized volatile anesthetics protect against renal ischemia reperfusion injury in rats in vivo and reduce necrosis in vitro via activation of ERK and Akt and by upregulating HSP70. In this study, we further deciphered the upstream cellular signaling mechanism(s) of volatile anesthetic-mediated antinecrotic effects in vitro. We hypothesized that volatile anesthetics perturb the structure of the plasma membrane lipid bilayer, causing externalization of phosphatidylserine (PS) to the outer surface on renal tubule cells leading to the increased generation of transforming growth factor-β1 (TGF-β1), a cytokine with antinecrotic properties. Methods and Results: In human proximal tubule (HK-2) cell culture, 16-hour exposure to volatile anesthetics (isoflurane, halothane, sevoflurane) caused membrane externalization of PS detected by positive annexin-V staining and increased the release of TGF-β1 into the cell culture media. Exogenous TGF-β1 induced protection and neutralizing TGF-β1 antibody prevented the cytoprotection by volatile anesthetics against hydrogen peroxide-induced HK-2 cell necrosis. Conclusions: Volatile anesthetics induce a cytoprotective signaling cascade in proximal tubule cells via membrane externalization of PS initiating TGF-β1-mediated cytoprotection.

Volatile Anesthetics and AKI

“…16,49 Volatile Anesthetics Release Renal Tubular TGF-b1 and Promote Plasma Membrane Caveolae Formation Disruption of the plasma membrane lipid bilayer by volatile anesthetics results in the translocation of phosphatidylserine from the inner leaflet to the outer leaflet of the plasma membrane (Figure 3). 50 Phosphatidylserine (PS) externalization in macrophages as well as in renal tubular epithelia leads to the release of a potent anti-inflammatory/antinecrotic molecule TGF-b1 in adjacent cells via ligation of PS receptors. 41,51,52 Indeed, TGF-b1 has been recognized as a key signaling molecule in the anti-inflammatory milieu of macrophages ingesting apoptotic cells.…”

Selective intrarenal human A1 adenosine receptor overexpression reduces acute liver and kidney injury after hepatic ischemia reperfusion in mice

“…Immunohistochemistry for huA 1 ARs was performed as described below. Finally, total RNA was extracted from renal cortices or liver and we performed reverse transcription-PCR assays for EGFP-huA 1 AR, EGFP and mouse GAPDH as described previously 14,17,18 (Table 1). The EGFP-huA 1 AR primer was designed with a sense primer that would anneal in the extreme 5 0 end of the A 1 AR portion of the construct, whereas the anti-sense primer anneals to the extreme 3 0 end of the EGFP portion.…”

Efficacy of Vitamin D3 in Patients With Diabetic Nephropathy: An Updated Meta-Analysis

“…Simultaneously, ACEI might enable activity of bradykinin to last long and alter renal hemodynamics, delaying fall of glomerular filtration rate (GFR) (37). Moreover, the interdiction of RAS by ACEI was suggested to restrain production and activity of TGF-β1 within nephridial tissues, which caused sclerosis and fibrosis of glomerular (38)(39)(40). Clinical studies also confirmed the meaningful role of ACEI (eg, benazepril and captopril) in doubling blood creatinine levels and improving prognosis of DN patients (41).…”