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Pretreatment with a novel Toll-like receptor 4 agonist attenuates renal ischemia-reperfusion injury.
- Source :
-
American journal of physiology. Renal physiology [Am J Physiol Renal Physiol] 2023 May 01; Vol. 324 (5), pp. F472-F482. Date of Electronic Publication: 2023 Mar 30. - Publication Year :
- 2023
-
Abstract
- Acute kidney injury (AKI) is common in surgical and critically ill patients. This study examined whether pretreatment with a novel Toll-like receptor 4 agonist attenuated ischemia-reperfusion injury (IRI)-induced AKI (IRI-AKI). We performed a blinded, randomized-controlled study in mice pretreated with 3-deacyl 6-acyl phosphorylated hexaacyl disaccharide (PHAD), a synthetic Toll-like receptor 4 agonist. Two cohorts of male BALB/c mice received intravenous vehicle or PHAD (2, 20, or 200 µg) at 48 and 24 h before unilateral renal pedicle clamping and simultaneous contralateral nephrectomy. A separate cohort of mice received intravenous vehicle or 200 µg PHAD followed by bilateral IRI-AKI. Mice were monitored for evidence of kidney injury for 3 days postreperfusion. Kidney function was assessed by serum blood urea nitrogen and creatinine measurements. Kidney tubular injury was assessed by semiquantitative analysis of tubular morphology on periodic acid-Schiff (PAS)-stained kidney sections and by kidney mRNA quantification of injury [neutrophil gelatinase-associated lipocalin ( Ngal ), kidney injury molecule-1 ( Kim-1 ), and heme oxygenase-1 ( Ho-1 )] and inflammation [interleukin-6 ( IL-6 ), interleukin-1β ( IL-1β ), and tumor necrosis factor-α ( Tnf-α )] using quantitative RT-PCR. Immunohistochemistry was used to quantify proximal tubular cell injury and renal macrophages by quantifying the areas stained with Kim-1 and F4/80 antibodies, respectively, and TUNEL staining to detect the apoptotic nuclei. PHAD pretreatment yielded dose-dependent kidney function preservation after unilateral IRI-AKI. Histological injury, apoptosis, Kim-1 staining, and Ngal mRNA were lower in PHAD-treated mice and IL-1β mRNA was higher in PHAD-treated mice. Similar pretreatment protection was noted with 200 mg PHAD after bilateral IRI-AKI, with significantly reduced Kim-1 immunostaining in the outer medulla of mice treated with PHAD after bilateral IRI-AKI. In conclusion, PHAD pretreatment leads to dose-dependent protection from renal injury after unilateral and bilateral IRI-AKI in mice. NEW & NOTEWORTHY Pretreatment with 3-deacyl 6-acyl phosphorylated hexaacyl disaccharide; a novel synthetic Toll-like receptor 4 agonist, preserves kidney function during ischemia-reperfusion injury-induced acute kidney injury.
- Subjects :
- Animals
Male
Mice
Kidney pathology
Lipocalin-2
Mice, Inbred C57BL
RNA, Messenger
Acute Kidney Injury etiology
Acute Kidney Injury pathology
Acute Kidney Injury prevention & control
Reperfusion Injury complications
Reperfusion Injury drug therapy
Reperfusion Injury pathology
Toll-Like Receptor 4 agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1466
- Volume :
- 324
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Renal physiology
- Publication Type :
- Academic Journal
- Accession number :
- 36995924
- Full Text :
- https://doi.org/10.1152/ajprenal.00248.2022