Heme oxygenase metabolites inhibit tubuloglomerular feedback (TGF).
Tubuloglomerular feedback (TGF) is the mechanism by which the macula densa (MD) senses increases in luminal NaCl concentration and sends a signal to constrict the afferent arteriole (Af-Art). The kidney expresses constitutively heme oxygenase-2 (HO-2) and low levels of HO-1. HOs release carbon monoxide (CO), biliverdin, and free iron. We hypothesized that renal HOs inhibit TGF via release of CO and biliverdin. Rabbit Af-Arts and attached MD were simultaneously microperfused in vitro. The TGF response was determined by measuring Af-Art diameter before and after increasing NaCl in the MD perfusate. When HO activity was inhibited by adding stannous mesoporphyrin (SnMP) to the MD perfusate, the TGF response increased from 2.1+/-0.2 to 4.1+/-0.4 microm (P=0.003, control vs. SnMP, n=7). When a CO-releasing molecule, (CORM-3; 50 microM), was added to the MD perfusate, the TGF response decreased by 41%, from 3.6+/-0.3 to 2.1+/-0.2 microm (P<0.001, control vs. CORM-3, n=12). When CORM-3 at 100 microM was added to the perfusate, it completely blocked the TGF response, from 4.2+/-0.4 to -0.2+/-0.3 microm (P<0.001, control vs. CORM-3, n=6). When biliverdin was added to the perfusate, the TGF response decreased by 79%, from 3.4+/-0.3 to 0.7+/-0.4 microm (P=0.001, control vs. biliverdin, n=6). The effects of SnMP and CORM-3 were not blocked by inhibition of nitric oxide synthase. We concluded that renal HO inhibits TGF probably via release of CO and biliverdin. HO regulation of TGF is a novel mechanism that could lead to a better understanding of the control of renal microcirculation and function.
Ren
YiLin
Y
Division of Hypertension and Vascular Research, Henry Ford Hospital, 2799 Grand Blvd., Detroit, MI 48202, USA.
D'Ambrosio
Martin A
MA
Wang
Hong
H
Liu
Ruisheng
R
Garvin
Jeffrey L
JL
Carretero
Oscar A
OA
D000818:Animals; D001160:Arterioles / Q000502:physiology; D001664:Biliverdine / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000201:enzymology*; D007684:Kidney Tubules / Q000201:enzymology*; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D011817:Rabbits; D012079:Renal Circulation / Q000502:physiology
D008665:Metalloporphyrins; C518404:stannous mesoporphyrin; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C105245:heme oxygenase-2; D001664:Biliverdine