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Role of macula densa adenosine triphosphate (ATP) in tubuloglomerular feedback

2004; Elsevier BV; Volume: 66; Issue: 4 Linguagem: Inglês

10.1111/j.1523-1755.2004.00911.x

1523-1755

Yilin Ren, Jeffrey L. Garvin, Ruisheng Liu, Oscar A. Carretero,

Receptor Mechanisms and Signaling

Role of macula densa adenosine triphosphate (ATP) in tubuloglomerular feedback.BackgroundRecent studies have shown that adenosine triphosphate (ATP) is liberated from macula densa cells in response to increased tubular NaCl in vitro. We tested the hypothesis that increased NaCl in the macula densa stimulates the release of ATP, resulting in extracellular formation of adenosine which is involved in signal transmission of the tubuloglomerular feedback response.MethodsRabbit afferent arterioles and attached macula densas were simultaneously microperfused in vitro. Tubuloglomerular feedback was induced by increasing macula densa Na/Cl from 11/10 to 81/80 mmol/L and was measured before and after treatment.ResultsWe first tested whether hydrolysis of ATP is required for tubuloglomerular feedback. When we enhanced conversion of ATP to adenosine by adding hexokinase or apyrase to the bath and arteriole lumen, the tubuloglomerular feedback response was augmented. During the control period, tubuloglomerular feedback decreased arteriole diameter by 2.2 ± 0.2 μm. In the presence of hexokinase, tubuloglomerular feedback decreased diameter by 3.4 ± 0.3 μm (N = 8) (P < 0.05, with vs. without hexokinase). In the apyrase group, tubuloglomerular feedback decreased diameter by 2.7 ± 0.4 μm during the control period. When apyrase was added, tubuloglomerular feedback decreased diameter by 4.7 ± 0.4 μm (N = 8) (P < 0.05, with vs. without apyrase). When hydrolysis of adenosine monophosphate (AMP) to adenosine was blocked by supplementing the bath with 100 μmol/L α,β-methylene adenosine 5′-diphosphate (MADP), an inhibitor of 5′-nucleotidase, tubuloglomerular feedback response was blocked and diameter remained unchanged. We next studied whether ATP released from the macula densa binds to P2 receptors and activates the tubuloglomerular feedback response. The P2 purinergic receptor inhibitor suramin was added to both arteriole lumen and bath. During the control period, tubuloglomerular feedback decreased diameter by 3.7 ± 0.5 μm. Suramin (100 μmol/L) did not significantly inhibit tubuloglomerular feedback, since in the presence of suramin diameter decreased by 3.8 ± 0.3 μm (N = 7). Finally, we added the adenosine A1 receptor inhibitor FK838 to both bath and lumen and found that it completely blocked high NaCl-induced tubuloglomerular feedback.ConclusionWe concluded that ATP released from the macula densa is broken down to form AMP in the extracellular space. AMP in turn is degraded by ecto-5′-nucleotidases to adenosine, which mediates signal transmission of the tubuloglomerular feedback response. Role of macula densa adenosine triphosphate (ATP) in tubuloglomerular feedback. Recent studies have shown that adenosine triphosphate (ATP) is liberated from macula densa cells in response to increased tubular NaCl in vitro. We tested the hypothesis that increased NaCl in the macula densa stimulates the release of ATP, resulting in extracellular formation of adenosine which is involved in signal transmission of the tubuloglomerular feedback response. Rabbit afferent arterioles and attached macula densas were simultaneously microperfused in vitro. Tubuloglomerular feedback was induced by increasing macula densa Na/Cl from 11/10 to 81/80 mmol/L and was measured before and after treatment. We first tested whether hydrolysis of ATP is required for tubuloglomerular feedback. When we enhanced conversion of ATP to adenosine by adding hexokinase or apyrase to the bath and arteriole lumen, the tubuloglomerular feedback response was augmented. During the control period, tubuloglomerular feedback decreased arteriole diameter by 2.2 ± 0.2 μm. In the presence of hexokinase, tubuloglomerular feedback decreased diameter by 3.4 ± 0.3 μm (N = 8) (P < 0.05, with vs. without hexokinase). In the apyrase group, tubuloglomerular feedback decreased diameter by 2.7 ± 0.4 μm during the control period. When apyrase was added, tubuloglomerular feedback decreased diameter by 4.7 ± 0.4 μm (N = 8) (P < 0.05, with vs. without apyrase). When hydrolysis of adenosine monophosphate (AMP) to adenosine was blocked by supplementing the bath with 100 μmol/L α,β-methylene adenosine 5′-diphosphate (MADP), an inhibitor of 5′-nucleotidase, tubuloglomerular feedback response was blocked and diameter remained unchanged. We next studied whether ATP released from the macula densa binds to P2 receptors and activates the tubuloglomerular feedback response. The P2 purinergic receptor inhibitor suramin was added to both arteriole lumen and bath. During the control period, tubuloglomerular feedback decreased diameter by 3.7 ± 0.5 μm. Suramin (100 μmol/L) did not significantly inhibit tubuloglomerular feedback, since in the presence of suramin diameter decreased by 3.8 ± 0.3 μm (N = 7). Finally, we added the adenosine A1 receptor inhibitor FK838 to both bath and lumen and found that it completely blocked high NaCl-induced tubuloglomerular feedback. We concluded that ATP released from the macula densa is broken down to form AMP in the extracellular space. AMP in turn is degraded by ecto-5′-nucleotidases to adenosine, which mediates signal transmission of the tubuloglomerular feedback response.