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Published in final edited form as: Hypertension. 2013 May 6;62(1):10.1161/HYPERTENSIONAHA.113.01164. doi: 10.1161/HYPERTENSIONAHA.113.01164

MECHANISM OF INHIBITION OF TUBULOGLOMERULAR FEEDBACK (TGF) BY CARBON MONOXIDE AND cGMP

YiLin Ren 1, Martin A D’Ambrosio 1, Jeffrey L Garvin 1, Hong Wang 1, Oscar A Carretero 1,*
PMCID: PMC3821182  NIHMSID: NIHMS482906  PMID: 23648700

Abstract

Tubuloglomerular feedback (TGF) is a mechanism that senses NaCl in the macula densa (MD) and causes constriction of the afferent arteriole (Af-Art). Carbon monoxide (CO), either endogenous or exogenous, inhibits TGF at least in part via cGMP. We hypothesize that CO in the MD, acting via both cGMP-dependent and - independent mechanisms, attenuates TGF by acting downstream from depolarization and Ca entry into the MD cells. In vitro, microdissected rabbit Af-Arts and their MD were simultaneously perfused and TGF was measured as the decrease in Af-Art diameter. MD depolarization was induced with ionophores, while adding the CO-releasing molecule CORM-3 to the MD perfusate at non-toxic concentrations. CORM-3 blunted depolarization-induced TGF at 50 μM, from 3.6±0.4 to 2.5±0.4 μm (P<0.01), and abolished it at 100 μM, to 0.1±0.1 μm (P<0.001, n=6). When cGMP generation was blocked by guanylyl cyclase inhibitor LY-83583 added to the MD, CORM-3 no longer affected depolarization-induced TGF at 50 μM (2.9±0.4 vs. 3.0±0.4 μm), but partially inhibited TGF at 100 μM (to 1.3±0.2 μm, P<0.05, n=9). Experiments using ETYA and indomethacin suggest arachidonic acid metabolites do not mediate the cGMP-independent effect of CO. We then added the calcium ionophore A23187 to the macula densa, which caused TGF (4.1±0.6 μM); A23187-induced TGF was inhibited by CORM-3 at 50 μM (1.9±0.6 μM, P<0.01) and 100 μM (0.2±0.5 μM, P<0.001, n=6). We conclude that CO inhibits TGF acting downstream from depolarization and calcium entry, acting via cGMP at low concentrations, but additional mechanisms of action may be involved at higher concentrations.

Keywords: carbon monoxide, cGMP, afferent arteriole, tubuloglomerular feedback, macula densa

Introduction

Tubuloglomerular feedback (TGF) is a major component of renal autoregulation, maintaining homeostasis by regulating renal blood flow and glomerular filtration at the single-nephron level1,2. TGF is mediated by the macula densa (MD), which detects changes in NaCl concentration in the distal tubule and transmits a feedback signal that constricts pre-glomerular vessels3,4. The cascade of events inside the MD starts with NaCl entry through the Na/K/2Cl type 2 cotransporter (NKCC2), followed by cell depolarization and calcium (Ca) entry1,5. These events have been studied by measuring changes in membrane potential and intracellular Ca concentration6-11. By using a technique developed by us consisting of simultaneous perfusion of a microdissected afferent arteriole (Af-Art) and its attached MD, we have been able to induce MD cell depolarization or Ca entry while simultaneously blocking NKCC2. We have shown that depolarization of the MD causes TGF12, and that increasing MD intracellular Ca, one of the late steps in the cascade, is both necessary and sufficient to induce TGF, since a cell-permeant Ca chelator can inhibit TGF, while a Ca ionophore can reproduce it13.

The factors that modulate TGF are multiple and less thoroughly studied (for review see3). One of the best established regulators of TGF is nitric oxide (NO), which acts at least in part via increases in cGMP14, and blunts NaCl entry to the MD15. This is not surprising since cGMP inhibits NKCC216. Carbon monoxide (CO) is another gas that, similarly to NO, also increases cGMP and exerts an important role in regulation of vascular tone and blood pressure17. We have previously shown that the enzymes that produce CO, heme oxygenase-1 (HO-1) and heme oxygenase-2 (HO-2), are both expressed in the MD18. Furthermore, we have shown that endogenous or exogenous CO in the MD inhibits TGF acting via cGMP19. Although current evidence suggests that CO, like NO, may inhibit TGF acting via cGMP and preventing MD depolarization, there have been no studies on whether CO or cGMP can inhibit TGF acting downstream from MD depolarization, and whether other mechanisms, independently of cGMP, participate in the inhibitory effect of CO on TGF.

We hypothesize that CO in the MD, acting via both cGMP-dependent and - independent mechanisms, attenuates TGF by acting downstream from depolarization and Ca entry into the MD cells. To address this hypothesis, we studied TGF elicited by MD depolarization or by a Ca ionophore in vitro and tested the effects of: a) dibutyryl cGMP, b) different concentrations of CO, in the presence and absence of a soluble guanylyl cyclase inhibitor in the MD.

Results

We first performed a time control experiment of depolarization-induced TGF. Four consecutive TGF responses were induced by increasing KCl in the MD perfusate from 4 to 50 mM in the presence of the potassium ionophore valinomycin (1 μM) while NKCC2 was inhibited with furosemide (100 μM). As shown in Fig. 1, the first TGF response decreased Af-Art diameter by 2.9 ± 0.1 μm (from 16.8 ± 0.7 to 13.9 ± 0.8 μm) when the MD perfusate was increased from 4 to 50 mM KCl. Subsequent TGF responses decreased Af-Art diameter by 3.1 ± 0.2, 3.0 ± 0.1, and 3.1 ± 0.2 μm. TGF responses were not significantly different, indicating that depolarization-induced TGF responses are stable and reproducible over time.

Fig. 1.

Fig. 1

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Tubuloglomerular feedback (TGF) was induced by switching luminal KCl in the macula densa (MD) from 4 to 50 mM in the presence of valinomycin four consecutive times. TGF responses were reproducible, indicating stability of the preparation.

We then determined the effect of CO on TGF elicited by MD depolarization. The first (control) TGF response was 3.6 ± 0.4 μm. Addition of CORM-3, a CO-releasing molecule to the MD perfusate at a concentration of 50 μM decreased TGF response by 30%, to 2.48 ± 0.37 μm, while CORM-3 100 μM completely inhibited TGF to 0.1 ± 0.1 μm (n = 6, p < 0.001; Fig. 2A).

Fig. 2.

Fig. 2

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A. Effect of the CO-releasing molecule CORM-3 (50 and 100 μM) on tubuloglomerular feedback (TGF) elicited by high KCl-induced depolarization. CORM-3 attenuated TGF in a dose-dependent manner. ** P < 0.01, *** P < 0.001. 2B. Effect of CORM-3 (100 μM) on tubuloglomerular feedback (TGF) elicited by nystatin-induced depolarization. CORM-3 completely prevented TGF. *** P < 0.001.

We have previously shown that depolarization of the MD with nystatin causes TGF even when NKCC2 is blocked12. Here we tested whether CO can also inhibit nystatin-induced TGF. We first induced TGF by increasing luminal NaCl concentration in the MD from 10 to 80 mM, causing Af-Art diameter to decrease by 3.0 ± 0.2 μm. We then returned NaCl to 10 mM and added nystatin (100 μM) to the MD lumen in the presence of furosemide, causing Af-Art diameter to decrease by 3.3 ± 0.2 μm. The TGF response induced by nystatin was not significantly different from that induced by high NaCl. When CORM-3 100 μM was added to the MD perfusate, nystatin-induced TGF was completely abolished, 0.4 ± 0.2 μm (n = 6; p < 0.001 with vs. without CORM-3, Fig. 2B). Taken together, these data indicate that CO inhibits TGF acting downstream from depolarization.

To test whether soluble guanylyl cyclase mediates the inhibitory effect of CO on depolarization-induced TGF, the soluble guanylyl cyclase inhibitor LY83583 (1 μM), was added to the MD perfusate. TGF induced by 50 mM KCl and valinomycin was 3.0 ± 0.5 μm. Blockade of cGMP generation with LY83583 did not affect depolarization-induced TGF (2.9 ± 0.4 μm), but completely prevented the inhibitory effect of CORM-3 50 μM (3.0 ± 0.4 μm). On the other hand, LY83583 only partially prevented the inhibitory effect of CORM-3 100 μM on depolarization-induced TGF, as CORM-3 100 μM was still able to reduce TGF to 1.3 ± 0.2 μm (n = 9; P < 0.02 LY83583 vs. LY83583 plus CORM-3 100 μM; Fig. 3). To confirm that cGMP inhibits TGF downstream from MD depolarization, the degradation-resistant cGMP analog dibutyryl-cGMP (500 μM) was added to the MD perfusate. Addition of dibutyryl-cGMP attenuated depolarization-induced TGF from 3.9 ± 0.6 μm to 0.6 ± 0.2 μm (n = 6; P < 0.002 with vs. without dibutyryl-cGMP; Fig. 4). These data suggest that CO acts via cGMP at low concentrations, but additional mechanisms of action may be involved at higher concentrations.

Fig. 3.

Fig. 3

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Effect of CORM-3 on depolarization-induced tubuloglomerular feedback (TGF) in the presence of the guanylyl cyclase inhibitor LY-83583 (1 μM). CORM-3 50 μM did not attenuate, but CORM-3 100 μM retained partial inhibitory effect on TGF. * P < 0.05.

Fig. 4.

Fig. 4

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Effect of the cGMP analog dibutyryl cGMP db-cGMP (500 μM) added to the macula densa (MD) on depolarization-induced tubuloglomerular feedback (TGF). db-cGMP inhibited TGF. ** P < 0.01.

To test whether prostaglandins mediate the cGMP-independent effect of CO on TGF, the cyclooxygenase inhibitor indomethacin (5×10−5 M) was added to the MD perfusate. TGF induced by 50 mM KCl and valinomycin was 3.0 ± 0.3 μm. Blockade of cGMP generation with LY83583 (10−5 M, i.e. 10-fold higher than in Fig. 3) did not affect depolarization-induced TGF (3.3 ± 0.5 μm), but partially prevented the inhibitory effect of CORM-3 100 μM on depolarization-induced TGF, as CORM-3 100 μM was still able to reduce TGF to 1.4 ± 0.2 μm (n = 6; P < 0.01 LY83583 vs. LY83583 plus CORM-3 100 μM). Addition of indomethacin did not block the inhibitory effect of CORM-3, as TGF under these conditions was 0.5 ± 0.5 μm (Fig. 5). Furthermore, to test whether any arachidonic acid metabolites from various pathways such as cytochrome P450, mediated the cGMP-independent effect of CO on TGF, we repeated this experiment but using the arachidonic acid analog ETYA (12.5 μM) instead of indomethacin. Similarly to indomethacin, ETYA did not block the inhibitory effect of CORM-3, as TGF responses under these conditions were 3.7 ± 0.3, 3.8 ± 0.1, 2.0 ± 0.2, and 0.3 ± 0.1 μm, respectively (n = 6, see http://hyper.ahajournals.org for Supplemental Fig. S1). These data suggest that the cGMP-independent effect of CO on TGF is not mediated by prostaglandins or other arachidonic acid metabolites.

Fig. 5.

Fig. 5

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Effect of CORM-3 100 μM on depolarization-induced tubuloglomerular feedback (TGF) in the presence of the guanylyl cyclase inhibitor LY-83583 (10 μM) and the COX inhibitor indomethacin (50 μM). Indomethacin did not prevent the effect of CORM-3 on TGF. ** P < 0.01.

It has been shown that MD cell membrane depolarization promotes Ca entry11 and that luminal perfusion with Ca and the Ca ionophore A23187 induced TGF13. To determine whether CO inhibits TGF downstream from the increase in intracellular Ca, we tested whether CO inhibits TGF induced by A23187 5 μM added to the MD perfusate. Control TGF was 4.1 ± 0.6 μm. Addition of CORM-3 50 μM decreased the TGF response to 1.9 ± 0.6 μm, while CORM-3 100 μM completely inhibited TGF, 0.2 ± 0.5 μm (n = 6, p < 0.001; Fig. 6A). To ensure that the observed attenuation of TGF was due to the addition of CORM-3 rather than a time effect causing waning of A23187-induced TGF, we performed a time control experiment. Ca ionophore-induced TGF remained stable during the experimental period (n = 6; Fig. 6B). These data suggest that CO inhibits TGF downstream from intracellular Ca increase.

Fig. 6.

Fig. 6

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A. Effect of CORM-3 on tubuloglomerular feedback (TGF) induced by a calcium ionophore A23187( 5 μM). CORM-3 inhibited TGF. ** P < 0.01, *** P < 0.001. 6B. Time control: Tubuloglomerular feedback (TGF) was induced by a calcium ionophore A23187 (5 μM). TGF responses were stable over time.

Discussion

We have previously reported that CO, either endogenous or exogenous, inhibits TGF, and that the mechanism for this effect is at least in part via the cGMP/PKG/cAMP pathway19. In the present study we found that: 1) depolarization of MD by either high KCl with valinomycin or nystatin initiates TGF; 2) CO blunts depolarization-induced TGF at a low concentration and abolishes it at a higher concentration; 3) blockade of cGMP generation with the guanylyl cyclase inhibitor LY-83583 completely prevents the inhibitory effect of low doses of CO on depolarization-induced TGF; 4) blockade of cGMP generation can only partially prevent the inhibitory effect of higher doses of CO; 5) addition of the cell-permeant, phosphodiesterase-resistant cGMP analog db-cGMP to the MD perfusate blunts depolarization-induced TGF; 6) neither indomethacin nor ETYA blocked the cGMP-independent effect of CO on TGF; 7) CO blunts Ca ionophore-induced TGF. We believe that our data are the first to show that CO inhibits TGF acting downstream from depolarization.

We have previously reported that the heme oxygenase (HO) system inhibits TGF, since inhibiting tubular HOs with SnMP potentiated TGF, while adding exogenous CO to the MD inhibited TGF. CO has profound effects on the intracellular signaling processes in many tissues. One of CO’s main mechanisms of action is by binding to the heme moiety of soluble guanylyl cyclase, thus leading to the stimulation of soluble guanylyl cyclase and subsequent elevation of cGMP20. In previous studies, we have shown that CO can attenuate TGF that was induced by increasing luminal NaCl in the MD19. Under those conditions, TGF depends on NKCC2 activity, and presumably, CO acts similarly to NO, inhibiting NKCC2 via the soluble guanylyl cyclase/cGMP system, i.e. CO would act pre-depolarization. To identify whether CO also acts post-depolarization, TGF responses were induced by high KCl and valinomycin, which cause MD membrane depolarization. We have evidence that during inhibition of NKCC2 with furosemide, depolarization of the MD elicits TGF12. In this study, we demonstrated that CO inhibits TGF induced by depolarization. To exclude possible spurious effects such as CO causing some interference with the ionophore valinomycin, we repeated our studies but with the cation ionophore nystatin, which causes sodium entry and membrane depolarization. Results resembled those of KCl/valinomycin-induced cell depolarization.

Interestingly, we found that inhibition of soluble guanylyl cyclase completely prevents the inhibitory effect of lower concentrations of CO on depolarization-induced TGF, but higher concentrations of CO recruit an additional, cGMP-independent mechanism that inhibits TGF. Based on our previous publications, we can exclude a toxic effect of CO on the macula densa, since the effect of CORM-3 100 μM was completely reversible21. We considered the possibility that high concentrations of CO could in fact still be acting through cGMP by outcompeting the soluble guanylyl cyclase inhibitor LY83583 for the binding to guanylyl cyclase, however, this is unlikely to be the case, since increasing the concentration of the inhibitor 10 fold did not abolish the remaining effect of CORM-3, thus confirming that CO has cGMP-independent effects on the MD.

The exact nature of the cGMP-independent effect of CORM-3 remains elusive. Most actions of CO, derive from its very high affinity to bind heme. Heme functions as the prosthetic group in hemeproteins, many of which are enzymes, such as guanylyl cyclase, and the binding of CO can affect their enzymatic activity22,23. At least two hemeproteins with enzymatic activity, cyclooxygenase (COX)24 and NADPH oxidase (NOX)25, are present in the MD and are known to modulate TGF, thus constituting potential targets for the cGMP-independent effect of CO on TGF. Two isoforms of COX (COX-1 and COX-2) are expressed in the MD, and there is evidence that COX-2-derived prostaglandins may attenuate TGF26,27. In addition, there is some evidence that CO may increase the formation of prostaglandins by activating COX at least in the brain28,29. We tested the possibility that part of the effect of CO was due to the release of arachidonic acid metabolites from the MD, either prostanoids (from COX) or CYP450 metabolites (since CYP450 is itself a hemeprotein). However, we found that blockade of COX did not prevent the effect of CO. To further test the participation of other arachidonic acid metabolites, we studied whether the arachidonic acid analog ETYA could prevent the effect of CO, but again the effect of CO was not prevented. These data suggest that an alternative target of CO may exist in the MD, but unlikely to be related to arachidonic acid metabolites.

Interestingly, both ETYA and indomethacin had the opposite effect from our hypothesis, i.e., not only did they fail to prevent the inhibitory effect of CO, but they themselves had an inhibitory effect on TGF induced by depolarization. Although not part of our hypothesis, these results also shed light on the role of arachidonic acid metabolites on TGF, that is in agreement with previous literature suggesting that arachidonic acid metabolites, including 20-HETE30 and thromboxane A 312, mediate the constrictor effect of TGF.

Although at the present time we do not have an explanation for the cGMP-independent effect of CO, one alternative is that CO may inhibit O −2 production, which would attenuate TGF. NOX are hemeproteins25 that produce superoxide (O −2). Two NOX isoforms are present in the MD, NOX2 and NOX4, with NOX2 being the main isoform responsible for O −2 production32. We have previously reported that O −2 in the MD potentiates TGF33. CO can bind the heme moiety in NOX, but unlike its effect on guanylyl cyclase and COX, binding of CO to NOX results in its inhibition34. Furthermore, it has been shown that CO can inhibit NOX in thick ascending limb cells, in a cGMP-independent manner35. Therefore, NOX represents a potential target for the effect of CO on TGF, in addition to soluble guanylyl cyclase.

When we added the soluble guanylyl cyclase inhibitor LY83583 to our preparation and induced MD cell depolarization, we found that LY83583 did not affect TGF, compared to control (vehicle) TGF (see Fig. 4). This was different from what we have previously found on NaCl-induced TGF14,18,19. One likely explanation is that both luminal NaCl and cell depolarization with KCl/valinomycin induce TGF, but only luminal NaCl induces the concomitant production of NO, which partially attenuates TGF. This assertion is based on our previous observations that luminal NaCl in the MD induces NO production14 in a manner that is independent of cell depolarization. Rather, luminal NaCl induces NO production via the Na/H exchanger, leading to an increase in intracellular pH, and increases in intracellular pH in turn lead to increased NO production by nitric oxide synthase 1, a pH-sensitive enzyme36. In addition, we have previously shown that MD depolarization induces the production of O −2 via NOX37, which would further reduce the bioavailability of NO. Thus, when TGF is induced by MD depolarization without simultaneously stimulating the production of NO/cGMP, it is not unexpected that the soluble guanylyl cyclase inhibitor is devoid of effect on basal TGF.

How depolarization induces TGF is not known, however, Ca appears to be involved. Peti-Peterdi and Bell11 showed that increasing lumen NaCl elevated cytosolic Ca concentration through a signaling pathway that includes Na/K/2Cl cotransport, basolateral membrane depolarization via Cl channels, and Ca entry through voltage-gated Ca channels. It was therefore reasoned that this large depolarization of membrane voltages, in the presence of high NaCl at the MD, could promote Ca entry across the basolateral membrane. We have shown that increasing Ca entry via the Na/Ca exchanger in the MD is necessary for induction of TGF13. Furthermore, induction of Ca entry by use of a Ca ionophore causes TGF, suggesting that the increase in intracellular Ca concentration is sufficient to stimulate the TGF13,38. Ca plays an important role in intracellular signal transduction by activating transport processes or stimulating the release of a chemical mediator. Previous micropuncture studies showed that a cytosolic Ca system is involved in MD cell signaling39. To determine whether CO inhibits TGF downstream from the increase in intracellular Ca, we perfused the lumen of the MD with the Ca ionophore A23187 and measured Af-Art diameter while adding CORM-3 to the MD perfusate. We found that CO inhibits TGF induced by the Ca ionophore in dose dependent manner.

Perspectives

Our present studies shed light on both the physiological cascade of events that occur in the MD and result in TGF, and the regulation of such cascade by CO. We have shown for the first time that TGF is subject to regulation downstream from MD cell depolarization by CO and cGMP. We have also expanded our knowledge of the actions of CO on TGF, which are complex, possibly involving effects both upstream and downstream from cell depolarization, both cGMP-dependent and cGMP-independent. By inhibiting TGF, CO will favor Af-Art dilation and increased renal blood flow, and these effects may help explain the antihypertensive and natriuretic actions of CO. These actions may be particularly relevant in conditions that increase oxidative stress and/or angiotensin II because such conditions are known inducers of HO-140, but decrease NO in the macula densa33,41. Furthermore, our findings may help explain how TGF is attenuated in diabetes, a condition with high O −2 (and presumably low MD NO bioavailability42) but with increased HO-1 activity43.

Supplementary Material

1

Novelty and Significance.

1. What Is New?

  • We studied mechanisms by which carbon monoxide affects tubuloglomerular feedback.

  • Our data are the first to show that CO inhibits TGF acting downstream from depolarization.

2. What Is Relevant?

  • The kidney plays a key role in high blood pressure. Kidney diseases cause hypertension, and hypertension can in turn damage the kidney.

  • By inhibiting TGF, CO will favor Af-Art dilation and increase renal blood flow. These effects may help explain the antihypertensive and natriuretic actions of CO.

  • Our studies will help to better understand the control of the renal microcirculation.

3. Summary (of the conclusions of the study)

To summarize, we found that: a) depolarization of MD by high KCl with valinomycin, nystatin and Ca ionophore initiates TGF; b) CO blunts depolarization-induced TGF at a low concentration and abolishes it at a higher concentration; c) blockade of cGMP generation completely prevents the inhibitory effect of low doses of CO; but only partially prevents the inhibitory effect of higher doses of CO; d) addition of db-cGMP to the MD blunts depolarization-induced TGF; e) neither indomethacin nor ETYA blocked the cGMP-independent effect of CO on TGF. We conclude that CO inhibits TGF acting downstream from depolarization and calcium entry, acting via cGMP at low concentrations, but additional mechanisms of action may be involved at higher concentrations.

Acknowledgements

None

Sources of Funding This study was supported by National Institutes of Health Grant HL-28982.

Footnotes

Conflicts of Interest/Disclosure(s) None.

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