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Published on: March 11, 2016
P2X7 receptor antagonism ameliorates renal dysfunction in a rat model of sepsis
Nishkantha Arulkumaran1,2,3, Marije L Sixma1, Sean Pollen1
1Bloomsbury Institute of Intensive Care Medicine, University College London, London, United Kingdom.
Abstract:
Sepsis is a major clinical problem associated with significant organ dysfunction and high mortality. The ATP-sensitive P2X7 receptor activates the NLRP3 inflammasome and is a key component of the innate immune system. We used a fluid-resuscitated rat model of fecal peritonitis and acute kidney injury (AKI) to investigate the contribution of this purinergic receptor to renal dysfunction in sepsis. Six and 24 h time-points were chosen to represent early and established sepsis, respectively. A selective P2X7 receptor antagonist (A-438079) dissolved in dimethyl sulfoxide (DMSO) was infused 2 h following induction of sepsis. Compared with sham-operated animals, septic animals had significant increases in heart rate (-1(-4 to 8)% vs. 21(12-26)%; P = 0.003), fever (37.4(37.2-37.6)°C vs. 38.6(38.2-39.0)°C; P = 0.0009), and falls in serum albumin (29(27-30)g/L vs. 26(24-28); P = 0.0242). Serum IL-1β (0(0-10)(pg/mL) vs. 1671(1445-33778)(pg/mL); P < 0.001) and renal IL-1β (86(50-102)pg/mg protein vs. 200 (147-248)pg/mg protein; P = 0.0031) were significantly elevated in septic compared with sham-operated animals at 6 h. Serum creatinine was elevated in septic animals compared with sham-operated animals at 24 h (23(22-25) μmol/L vs. 28 (25-30)μmol/L; P = 0.0321). Renal IL-1β levels were significantly lower in A-438079-treated animals compared with untreated animals at 6 h (70(55-128)pg/mg protein vs. 200(147-248)pg/mg protein; P = 0.021). At 24 h, compared with untreated animals, A-438079-treated animals had more rapid resolution of tachycardia (22(13-36)% vs. -1(-6 to 7)%; P = 0.019) and fever (39.0(38.6-39.1)°C vs. 38.2(37.6-38.7)°C; P < 0.024), higher serum albumin (23(21-25)g/L vs. (27(25-28)g/L); P = 0.006), lower arterial lactate (3.2(2.5-4.3)mmol/L vs. 1.4(0.9-1.8)mmol/L; P = 0.037), and lower serum creatinine concentrations (28(25-30)μmol/L vs. 22(17-27)μmol/L; P = 0.019). P2X7 A treatment ameliorates the systemic inflammatory response and renal dysfunction in this clinically relevant model of sepsis-related AKI.
Insights
Sepsis causes organ dysfunction and high mortality. Targeting the P2X7 receptor with A-438079 reduces inflammation and improves kidney function in a sepsis model, offering a potential therapeutic strategy.
Area of Science:
- Immunology
- Nephrology
- Pharmacology
Background:
- Sepsis is a life-threatening condition characterized by organ dysfunction and high mortality rates.
- The ATP-sensitive P2X7 receptor plays a crucial role in the innate immune system by activating the NLRP3 inflammasome.
- Acute kidney injury (AKI) is a common and severe complication of sepsis.
Purpose of the Study:
- To investigate the role of the P2X7 receptor in sepsis-induced renal dysfunction.
- To evaluate the therapeutic potential of a selective P2X7 receptor antagonist (A-438079) in a rat model of sepsis-related AKI.
Main Methods:
- A fluid-resuscitated rat model of fecal peritonitis and AKI was established.
- Septic and sham-operated groups were compared at 6 and 24 hours post-induction.
- A P2X7 receptor antagonist (A-438079) was administered 2 hours after sepsis induction.
Main Results:
- Sepsis induced significant increases in heart rate, fever, and serum IL-1β levels, along with elevated serum creatinine at 24 hours.
- Treatment with A-438079 significantly reduced renal IL-1β levels at 6 hours.
- At 24 hours, A-438079-treated rats showed improved physiological parameters, including resolved tachycardia and fever, higher serum albumin, lower arterial lactate, and reduced serum creatinine compared to untreated septic rats.
Conclusions:
- The P2X7 receptor contributes significantly to the systemic inflammatory response and renal dysfunction observed in sepsis.
- Pharmacological antagonism of the P2X7 receptor with A-438079 demonstrates a protective effect against sepsis-induced AKI.
- Targeting the P2X7 receptor represents a promising therapeutic avenue for managing sepsis and its associated organ damage.
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