Heme oxygenase metabolites inhibit tubuloglomerular feedback in vivo.
Tubuloglomerular feedback (TGF) is a renal autoregulatory mechanism that constricts the afferent arteriole in response to increases in distal NaCl. Heme oxygenases (HO-1 and HO-2) release carbon monoxide (CO) and biliverdin, which may help control renal function. We showed in vitro that HO products inhibit TGF; however, we do not know whether this also occurs in vivo or the mechanism(s) involved. We hypothesized that in vivo HO-1 and HO-2 in the nephron inhibit TGF via release of CO and biliverdin. We first performed laser capture microdissection followed by real-time PCR and found that both HO-1 and HO-2 are expressed in the macula densa. We next performed micropuncture experiments in vivo on individual rat nephrons, adding different compounds to the perfusate, and found that an HO inhibitor, stannous mesoporphyrin (SnMP), potentiated TGF (P < 0.05, SnMP vs. control). The CO-releasing molecule (CORM)-3 partially inhibited TGF at 50 μmol/l (P < 0.01, CORM-3 vs. control) and blocked it completely at higher doses. A soluble guanylyl cyclase (sGC) inhibitor, LY83583, blocked the inhibitory effect of CORM-3 on TGF. Biliverdin also partially inhibited TGF (P < 0.01, biliverdin vs. control), most likely attributable to decreased superoxide (O(2)(-)) because biliverdin was rendered ineffective by tempol, a O(2)(-) dismutase mimetic. We concluded that HO-1 and HO-2 in the nephron inhibit TGF by releasing CO and biliverdin. The inhibitory effect of CO on TGF is mediated by the sGC/cGMP signaling pathway, whereas biliverdin probably acts by reducing O(2)(-).
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan, USA.
Hong
H
Wang
Jeffrey L
JL
Garvin
Martin A
MA
D'Ambrosio
John R
JR
Falck
Pablo
P
Leung
Ruisheng
R
Liu
YiLin
Y
Ren
Oscar A
OA
Carretero
D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D001664:Biliverdine / Q000037:antagonists & inhibitors; D002248:Carbon Monoxide / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005246:Feedback / Q000187:drug effects*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000201:enzymology*; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D000071756:Soluble Guanylyl Cyclase; D013113:Spin Labels; D013481:Superoxides / Q000378:metabolism
D000634:Aminoquinolines; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D009942:Organometallic Compounds; D018160:Receptors, Cytoplasmic and Nuclear; D013113:Spin Labels; C518404:stannous mesoporphyrin; C476530:tricarbonylchloro(glycinato)ruthenium(II); D013481:Superoxides; D002248:Carbon Monoxide; C041715:6-anilino-5,8-quinolinedione; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C105245:heme oxygenase-2; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D001664:Biliverdine; C001803:tempol
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