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Highly Sensitive Measurement of Glomerular Permeability in Mice with Fluorescein Isothiocyanate-polysucrose 70
Published on: August 9, 2019
Inhibition of COX-1 attenuates the formation of thromboxane A2 and ameliorates the acute decrease in glomerular
Katharina Mederle1, Manuel Meurer2, Hayo Castrop1
1Institute of Physiology, University of Regensburg, Regensburg, Germany; and.
Abstract:
Thromboxane (Tx) A2 has been suggested to be involved in the development of sepsis-induced acute kidney injury (AKI). Therefore, we investigated the impact of cyclooxygenase (COX)-1 and COX-2 activity on lipopolysaccharide (LPS)-induced renal TxA2 formation, and on endotoxemia-induced AKI in mice. Injection of LPS (3 mg/kg ip) decreased glomerular filtration rate (GFR) and the amount of thrombocytes to ∼50% of basal values after 4 h. Plasma and renocortical tissue levels of TxB2 were increased ∼10- and 1.7-fold in response to LPS, respectively. The COX-1 inhibitor SC-560 attenuated the LPS-induced fall in GFR and in platelet count to ∼75% of basal levels. Furthermore, SC-560 abolished the increase in plasma and renocortical tissue levels of TxB2 in response to LPS. The COX-2 inhibitor SC-236 further enhanced the LPS-induced decrease in GFR to ∼40% of basal values. SC-236 did not alter thrombocyte levels nor the LPS-induced increase in plasma and renocortical tissue levels of TxB2. Pretreatment with clopidogrel inhibited the LPS-induced drop in thrombocyte count, but did not attenuate the LPS-induced decrease in GFR and the increase in plasma TxB2 levels. This study demonstrates that endotoxemia-induced TxA2 formation depends on the activity of COX-1. Our study further indicates that the COX-1 inhibitor SC-560 has a protective effect on the decrease in renal function in response to endotoxin. Therefore, our data support a role for TxA2 in the development of AKI in response to LPS.
Insights
Cyclooxygenase-1 (COX-1) activity drives thromboxane A2 (TxA2) production during sepsis-induced acute kidney injury (AKI). Inhibiting COX-1 with SC-560 protected against kidney dysfunction, suggesting TxA2
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Sepsis-induced acute kidney injury (AKI) is a critical condition often linked to thromboxane A2 (TxA2) involvement.
- Understanding the specific cyclooxygenase (COX) pathways mediating TxA2 production in AKI is crucial for therapeutic development.
Purpose of the Study:
- To investigate the roles of COX-1 and COX-2 in lipopolysaccharide (LPS)-induced renal TxA2 formation and AKI in mice.
- To evaluate the therapeutic potential of COX inhibitors in mitigating endotoxemia-induced kidney damage.
Main Methods:
- Mice were injected with LPS to induce endotoxemia and AKI.
- Glomerular filtration rate (GFR), platelet counts, and TxB2 levels (plasma and kidney tissue) were measured.
- Specific COX-1 (SC-560) and COX-2 (SC-236) inhibitors, as well as clopidogrel, were administered.
Main Results:
- LPS injection significantly reduced GFR and platelet counts, while increasing TxB2 levels.
- The COX-1 inhibitor SC-560 attenuated the decrease in GFR and platelet count, and blocked TxB2 elevation.
- The COX-2 inhibitor SC-236 exacerbated the LPS-induced GFR reduction without affecting TxB2 levels.
Conclusions:
- Endotoxemia-induced TxA2 formation is primarily mediated by COX-1 activity.
- The COX-1 inhibitor SC-560 demonstrated a protective effect against LPS-induced AKI in mice.
- These findings support a significant role for TxA2 in the pathogenesis of sepsis-induced AKI and highlight COX-1 as a potential therapeutic target.
