TY - JOUR
T1 - Mechanisms of carbon monoxide attenuation of tubuloglomerular feedback
AU - Ren, Yilin
AU - D'Ambrosio, Martin A.
AU - Wang, Hong
AU - Falck, J R
AU - Peterson, Edward L.
AU - Garvin, Jeffrey L.
AU - Carretero, Oscar A.
PY - 2012/6
Y1 - 2012/6
N2 - Carbon monoxide (CO) is a physiological messenger with diverse functions in the kidney, including controlling afferent arteriole tone both directly and via tubuloglomerular feedback (TGF). We have reported that CO attenuates TGF, but the mechanisms underlying this effect remain unknown. We hypothesized that CO, acting via cGMP, cGMP-dependent protein kinase, and cGMP-stimulated phosphodiesterase 2, reduces cAMP in the macula densa, leading to TGF attenuation. In vitro, microdissected rabbit afferent arterioles and their attached macula densa were simultaneously perfused. TGF was measured as the decrease in afferent arteriole diameter elicited by switching macula densa NaCl from 10 to 80 mmol/L. Adding a CO-releasing molecule (CORM-3, 5×10 -5 mol/L) to the macula densa blunted TGF from 3.3±0.3 to 2.0±0.3 μm (P<0.001). The guanylate cyclase inhibitor LY-83583 (10 -6 mol/L) enhanced TGF (5.8±0.6 μm; P<0.001 versus control) and prevented the effect of CORM-3 on TGF (LY-83583+CORM-3, 5.5±0.3 μm). Similarly, the cGMP-dependent protein kinase inhibitor KT-5823 (2×10 -6 mol/L) enhanced TGF and prevented the effect of CORM-3 on TGF (KT-5823, 6.0±0.7 μm; KT-5823+CORM-3, 5.9±0.8 μm). However, the phosphodiesterase 2 inhibitor BAY-60-7550 (10 -6 mol/L) did not prevent the effect of CORM-3 on TGF (BAY-60-7550, 4.07±0.31 μm; BAY-60-7550+CORM-3, 1.84±0.31 μm; P<0.001). Finally, the degradation-resistant cAMP analog dibutyryl-cAMP (10 -3 mol/L) prevented the attenuation of TGF by CORM-3 (dibutyryl-cAMP, 4.6±0.5 μm; dibutyryl-cAMP+CORM-3, 5.0±0.6 μm). We conclude that CO attenuates TGF by reducing cAMP via a cGMP-dependent pathway mediated by cGMP-dependent protein kinase rather than phosphodiesterase 2. Our results will lead to a better understanding of the mechanisms that control the renal microcirculation.
AB - Carbon monoxide (CO) is a physiological messenger with diverse functions in the kidney, including controlling afferent arteriole tone both directly and via tubuloglomerular feedback (TGF). We have reported that CO attenuates TGF, but the mechanisms underlying this effect remain unknown. We hypothesized that CO, acting via cGMP, cGMP-dependent protein kinase, and cGMP-stimulated phosphodiesterase 2, reduces cAMP in the macula densa, leading to TGF attenuation. In vitro, microdissected rabbit afferent arterioles and their attached macula densa were simultaneously perfused. TGF was measured as the decrease in afferent arteriole diameter elicited by switching macula densa NaCl from 10 to 80 mmol/L. Adding a CO-releasing molecule (CORM-3, 5×10 -5 mol/L) to the macula densa blunted TGF from 3.3±0.3 to 2.0±0.3 μm (P<0.001). The guanylate cyclase inhibitor LY-83583 (10 -6 mol/L) enhanced TGF (5.8±0.6 μm; P<0.001 versus control) and prevented the effect of CORM-3 on TGF (LY-83583+CORM-3, 5.5±0.3 μm). Similarly, the cGMP-dependent protein kinase inhibitor KT-5823 (2×10 -6 mol/L) enhanced TGF and prevented the effect of CORM-3 on TGF (KT-5823, 6.0±0.7 μm; KT-5823+CORM-3, 5.9±0.8 μm). However, the phosphodiesterase 2 inhibitor BAY-60-7550 (10 -6 mol/L) did not prevent the effect of CORM-3 on TGF (BAY-60-7550, 4.07±0.31 μm; BAY-60-7550+CORM-3, 1.84±0.31 μm; P<0.001). Finally, the degradation-resistant cAMP analog dibutyryl-cAMP (10 -3 mol/L) prevented the attenuation of TGF by CORM-3 (dibutyryl-cAMP, 4.6±0.5 μm; dibutyryl-cAMP+CORM-3, 5.0±0.6 μm). We conclude that CO attenuates TGF by reducing cAMP via a cGMP-dependent pathway mediated by cGMP-dependent protein kinase rather than phosphodiesterase 2. Our results will lead to a better understanding of the mechanisms that control the renal microcirculation.
KW - Afferent arteriole
KW - Macula densa
KW - TGF
KW - cAMP
KW - cGMP
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UR - http://www.scopus.com/inward/citedby.url?scp=84861529142&partnerID=8YFLogxK
U2 - 10.1161/HYPERTENSIONAHA.112.192120
DO - 10.1161/HYPERTENSIONAHA.112.192120
M3 - Article
C2 - 22508834
AN - SCOPUS:84861529142
SN - 0194-911X
VL - 59
SP - 1139
EP - 1144
JO - Hypertension
JF - Hypertension
IS - 6
ER -