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Endothelin-Induced Increased Nitric Oxide Mediates Augmented Distal Nephron Acidification as a Result of Dietary Protein

Donald E. Wesson^*,, Jan Simoni and Sharma Prabhakar^*,

Texas Tech University Health Sciences Center, Departments of ^* Internal Medicine, Physiology, and Surgery, Texas Tech University School of Medicine, Lubbock, Texas

Address correspondence to: Dr. Donald E. Wesson, Texas Tech University Health Sciences Center, Renal Section, 3601 4th Street, Lubbock, TX 79430. Phone: 806-743-3107; Fax: 806-743-3177; E-mail: donald.wesson{at}ttuhsc.edu

Received for publication July 26, 2005. Accepted for publication November 22, 2005.

	Abstract

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Tested was the hypothesis that enhanced nitric oxide (NO) production that is stimulated by increased renal endothelin activity mediates decreased distal nephron HCO₃ secretion that is induced by dietary protein. Munich-Wistar rats that ate minimum electrolyte diets with 50% casein-provided protein (HiPro) compared with controls that ate 20% protein for 3 wk had higher urine excretion of endothelin-1 (80 ± 15.7 versus 29 ± 3.9 fmol/kg body wt per d; P < 0.02) and of the NO metabolites NO₂/NO₃ (21.2 ± 1.9 versus 14.9 ± 0.8 µmol/kg body wt per d; P < 0.03). Bosentan, an endothelin A/B receptor antagonist, reduced HiPro rats’ urine excretion of net acid (5859 ± 654 versus 8017 ± 1103 µmol/d; P < 0.03, paired t test) and NO₂/NO₃ (18.1 ± 1.1 versus 22.9 ± 2.0 µmole/kg body wt per d; P < 0.05, paired t test). N-nitro-l-arginine methyl ester (L-NAME), an NO synthase inhibitor, also decreased urine net acid excretion (6621 ± 717 versus 8449 ± 1086 µmol/d; P < 0.05, paired t test) but was not additive to bosentan. L-NAME increased in situ late distal nephron HCO₃ delivery in HiPro rats (18.8 ± 1.7 versus 9.6 ± 1.4 pmol/mm per min; P < 0.001) that was mediated by increased distal nephron HCO₃ secretion (–7.2 ± 0.7 versus –3.5 ± 0.4 pmol/mm per min; P < 0.001) without changes in distal nephron transtubule HCO₃ permeability or H⁺ secretion. Bosentan decreased H⁺ secretion and increased HCO₃ secretion in the distal nephron of HiPro rats, but L-NAME had no additive effect on either component. The data support that dietary protein augments distal nephron acidification through decreased HCO₃ secretion that is mediated through endothelin-stimulated NO.

	Introduction

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Enhanced renal endothelin production that is induced by increased dietary protein augments distal nephron acidification through increased H⁺ secretion and decreased HCO₃ secretion (1,2). Augmented distal nephron H⁺ secretion in this setting is due to an endothelin-stimulated increase in Na⁺/H⁺ exchange (1,2) and to endothelin-induced increased aldosterone secretion that in turn stimulates H⁺-ATPase activity (2), supporting the important role for endothelin as a mediator of augmented distal nephron H⁺ secretion induced by increased dietary protein. Although endothelin receptor antagonism inhibits the decrease in distal nephron HCO₃ secretion that is induced by dietary protein (1,2) and systemic endothelin infusion reduces distal nephron HCO₃ secretion that is induced by dietary HCO₃ (3), the mechanism by which endothelin reduces distal nephron HCO₃ secretion is not known. In addition to increasing renal production of endothelin, increased dietary protein increases urine excretion of nitric oxide (NO) metabolites (4). Furthermore, endothelin increases renal NO production (5), and NO increases acidification in the proximal (6) and distal (7) nephron. Consequently, we tested the hypothesis that increased renal endothelin production that is induced by increased dietary protein reduces distal nephron HCO₃ secretion through increased NO.

	Materials and Methods

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Animals and Diet Protocol
Male and female Munich-Wistar rats (Harlan Sprague-Dawley, Houston, TX; 200 to 228 g) ate standard rat chow (Prolab RMH 2500 with 23% protein, Purina, Indianapolis, IN) for 1 wk, then ate a custom minimum electrolyte diet with protein as purified high nitrogen casein (ICN Nutritional Biochemicals, Cleveland, OH) for 3 wk and drank distilled H₂O ad libitum. Rats that were on the high-protein diet (HiPro) ate custom diet with 50% protein, and controls ate 20%. In preliminary studies, similar-weight rats ate 24.6 ± 0.9 and 27.1 ± 1.2 g/d, respectively (n = 4, P = 0.15), so all rats received 24 g/d diet to ensure similar diet intake and complete ingestion of drug mixed with diet in rats that were given drugs. Some received bosentan (Actelion, Allschwil, Switzerland), a nonpeptide endothelin A/B receptor antagonist (8), mixed with study diet at 100 mg/kg body wt per d. This oral dose blocks action of pressor doses of intravenous big ET-1 for >24 h (8). Preliminary studies determined that the minimal chronic dose of the NO synthase (NOS) inhibitor N-nitro-l-arginine methyl ester (L-NAME) that reduced urine net acid excretion (NAE) in paired HiPro rats (6451 ± 785 versus 8488 ± 904 µmol/d; n = 4 each; P < 0.03, paired t) was 25 mg/kg body wt per d L-NAME and was the dose used in these studies.

Urine NAE in Conscious Animals
Daily urine NAE was measured (9) in a 24-h sample that was collected on protocol day 28 in eight each of HiPro rats and controls in metabolic cages. The effect of endothelin receptor blockade and of NOS inhibition on urine NAE was examined in paired and separate groups of eight each (four not ingesting and four ingesting) of HiPro rats and control.

Arterial Total CO₂ in Conscious Animals
Arterial plasma total CO₂ (TCO₂) from a chronic carotid arterial catheter in eight each of awake, gently restrained, and calm HiPro rats and controls was measured by ultrafluorometry (see below) to assess the effect of 3 wk of HiPro on this acid-base parameter.

GFR in Conscious Animals
GFR was measured in eight each of awake, gently restrained, and calm HiPro rats and controls with standard clearance techniques using ³H-inulin as described previously in anesthetized animals (10). The effect of endothelin receptor blockade and of NOS inhibition on GFR was examined in paired and separate groups of eight each (four not ingesting and four ingesting inhibitor) of HiPro rats and controls.

Micropuncture Protocol
Accessible rat distal nephron segments underwent paired free-flow fluid collections from late then early portions (9) or underwent in vivo microperfusion (11). In situ early distal flow rate for HiPro rats and controls was 9.4 ± 0.7 (n = 6) and 6.4 ± 0.4 nl/min (n = 8), respectively. Consequently, distal nephrons of both HiPro rats and controls were perfused at 6 and 9 nl/min with a Hampel pump. When comparisons were done within HiPro rats or controls, only the 9- or 6-nl/min flow rate was used. Distal nephron transepithelial potential difference was measured to calculate blood-to-lumen HCO₃ permeability (11). Tubule segment length was determined using an injected latex cast (11). Stellate vessel plasma [HCO₃] was measured to determine peritubular blood-to-lumen HCO₃ gradient for calculating transepithelial H⁺/HCO₃ passive permeability (11). Diet but not H₂O was withheld the evening before micropuncture to yield higher baseline HCO₃ reabsorption (12), as done previously (11).

Perfusion solutions are in Table 1. Standard perfusate (solution 1) contained 5 mM HCO₃ to approximate early distal tubule [HCO₃] in situ (11). Solution 2 was HCO₃^–- and chloride (Cl^–)-free and contained acetazolamide to inhibit transtubule H⁺/HCO₃ transport and thereby determine passive blood-to-lumen H⁺/HCO₃ permeability (11) that was used to calculate passive blood-to-lumen HCO₃ secretion when perfusing with the HCO₃-containing solution 1 (11). We also measured Cl^–-dependent luminal HCO₃ accumulation with solution 3 having Cl^– but no HCO₃ to allow Cl^–-dependent HCO₃ secretion (11). Solution 3 also permitted determination of "apparent" blood-to-lumen HCO₃ permeability to calculate distal nephron H⁺/HCO₃ secretion when perfusing with HCO₃-containing solution 1 (11). The latter value is "total" HCO₃ secretion whereas "net" HCO₃ secretion is total HCO₃ secretion minus the passive component (calculated with permeability determined with solution 3). All perfusing solutions contained raffinose to minimize fluid transport and gluconate substituted for Cl^– when necessary (11).

Statistical Analyses
Immediately after experiment termination, initial and collected perfusate, as well as stellate vessel plasma samples, were analyzed for inulin (11) and for TCO₂ using flow-through ultrafluorometry (13) as done previously (14). All tubule fluid and plasma TCO₂ were measured on the experimental day by comparing sample fluorescence (corrected for H₂O blank) to a standard curve (14). This technique actually measures TCO₂, but we refer to this measured value as HCO₃ for simplicity.

[ET-1] in urine was measured using a RIA kit (Peninsula Laboratories, Inc., Belmont, CA) after disposable column extraction (Sep-Pak C18, Milford, MA) preconditioned with methanol, H₂O, and acetic acid as described (15) and as done previously (16).

Urine [NO] was measured as described (17). Briefly, urine samples first were centrifuged to remove all suspended and undissolved particles and deproteinated by ethanol precipitation. The samples were diluted 1:20 before measurement. NO was assayed by measuring NO₃ and NO₂, stable end products of NO, by an NO analyzer (Sievers Nitric Oxide Analyzer; Ionics Instruments, Boulder, CO) that uses chemiluminescence. Diluted samples (10 µl) were injected into a purge vessel that contained vanadium that converted NO₃ and NO₂ to NO. NO in the vessel then was propelled by nitrogen into a reaction chamber in which NO was oxidized to NO₂ by oxygen. Chemiluminescence associated with this reaction was displayed in millivolts on the NO analyzer. The signal associated with such a reaction was acquisitioned and analyzed by NO analysis software that digitizes the data to yield the amount of NO in the sample in micromoles. Every sample was measured in triplicate, and the average of the three readings was taken as the representative of NO content in the sample. The NO activity of the diluting nano-pure water was subtracted from each sample to obtain the true NO content of the sample.

Data were expressed as means ± SEM. One to two distal nephron segments were perfused per animal. When two tubules were perfused, results were averaged to yield a single animal value. Paired perfusions of the same tubule were compared using paired t test; otherwise, ANOVA was used for multiple group comparisons. Bonferroni method was used for multiple comparisons (P < 0.05) of the same parameter among groups that contained eight each of HiPro rats and controls unless otherwise stated.

	Results

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Effect of HiPro on Urine Flow and GFR in Conscious Rats
Although daily food intake was identical between HiPro rats and controls, HiPro rats had higher urine flow (40 ± 4 versus 14 ± 2 ml/d, respectively; P < 0.001) and GFR (2367 ± 221 versus 1550 ± 139 µl/min; P < 0.01).

Effect of HiPro on Plasma TCO₂ and Urine NAE of Conscious Rats
HiPro rats had lower plasma TCO₂ by ultrafluorometry (23.0 ± 0.7 versus 25.2 ± 0.6 mM; P < 0.04) and higher urine NAE (8254 ± 1047 versus 4293 ± 476 µmol/d; P < 0.004) than controls. Table 2 shows that higher NAE in HiPro rats was mediated by higher U_NH4+V (P < 0.001) and lower U_HCO3V (P > 0.001), but U_TAV was similar (P = 0.14).

View larger version (19K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Distal nephron net HCO3 reabsorption (Net JHCO3) and its components, HCO3 and H+ secretion, by in vivo microperfusion in rats that were fed a high-protein diet (HiPro) and controls after 3 wk of diet. Positive/negative values indicate reabsorption/secretion, respectively. *P < 0.05 versus controls.

View larger version (13K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 2. Urine endothelin-1 (ET-1; left) and nitric oxide metabolites (NO2/NO3; right) excretion in conscious HiPro rats and controls after 3 wk. *P < 0.05 versus controls.

View larger version (16K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 3. Plasma total CO2 (TCO2) in control and HiPro rats 3 wk after ingesting diets without (baseline) or with the indicated inhibitors or their combination. *P < 0.05 versus respective baseline.

Effect of ET-1 Receptor Blockade and NOS Inhibition on HiPro-Induced Increases in Distal Nephron Acidification
Table 3 shows that bosentan, L-NAME, and their combination increased in situ late distal [HCO₃] and late distal HCO₃ delivery in HiPro rats but not in controls. Table 3 also shows that these inhibitors and their combination reduced distal nephron net and fractional HCO₃ reabsorption in HiPro rats but not in controls. Distal nephron net HCO₃ reabsorption was not different among controls that ingested bosentan, L-NAME, or their combination compared with controls that did not ingest either agent. The inhibitor-induced increases in in situ HCO₃ deliveries to the late distal nephron of HiPro rats were associated with inhibitor-induced differences in HCO₃ deliveries to the early distal nephron, complicating interpretation of these data from these free-flow micropuncture studies as to the mechanism(s) of these inhibitor-induced increased HCO₃ deliveries to the late distal nephron of HiPro rats. Specifically, these free-flow micropuncture studies did not determine whether the inhibitor-induced increase in HCO₃ deliveries were mediated by inhibitor-induced increases in blood-to-lumen HCO₃ permeability, by decreased H⁺ secretion, and/or by increased HCO₃ secretion. For addressing these mechanistic concerns, these free-flow micropuncture studies were followed by in vivo microperfusion studies in which distal nephrons of HiPro rats and controls were perfused with solutions of identical [HCO₃] and at identical perfusion rates. This technique also allows estimation of transtubule HCO₃ permeability and for calculation of the components of distal nephron net HCO₃ reabsorption, H⁺ and HCO₃ secretion (see Materials and Methods).

Figure 4 shows no difference in peritubular blood-to-lumen passive permeability within HiPro rats and controls when animals that ingested inhibitor were compared with their respective baseline. Furthermore, there was no difference in permeability between HiPro rats and controls at baseline or with either inhibitor or their combination. Figure 5 shows no differences in distal nephron acidification by in vivo microperfusion among controls that ingested either inhibitor or their combination compared with baseline. By contrast, Figure 6 shows that HiPro rats that ingested bosentan had lower distal nephron net HCO₃ reabsorption (22.4 ± 1.9 versus 37.8 ± 3.2 pmol/mm per min; P < 0.001) that was due to greater HCO₃ secretion (–6.0 ± 0.7 versus –3.5 ± 0.4 pmol/mm per min; P < 0.008) and lower H⁺ secretion (28.4 ± 2.4 versus 41.3 ± 4.0 pmol/mm per min; P = 0.016). In Figure 7, HiPro rats that ingested L-NAME had greater distal nephron HCO₃ secretion (–7.2 ± 0.7 versus –3.5 ± 0.4 pmol/mm per min; P < 0.001), but distal nephron net HCO₃ reabsorption (31.7 ± 3.0 versus 37.8 ± 3.2 pmol/mm per min; P = 0.19) and H⁺ secretion (38.8 ± 3.7 versus 41.3 ± 4.0 pmol/mm per min; P = 0.46) were similar to HiPro rats that did not ingest L-NAME. Figure 8 shows that distal nephron net HCO₃ reabsorption (19.9 ± 1.8 versus 22.4 ± 1.9 pmol/mm per min; P = 0.36), HCO₃ secretion (–7.1 ± 0.8 versus –6.0 ± 0.7 pmol/mm per min; P = 0.32), and H⁺ secretion (26.8 ± 2.5 versus 28.4 ± 2.4 pmol/mm per min; P = 0.65) were similar in HiPro rats that simultaneously ingested bosentan+L-NAME compared with those that ingested bosentan alone.

View larger version (20K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 4. Blood-to-lumen passive HCO3 permeability determined by in vivo microperfusion in HiPro and control animals 3 wk after ingesting diets without (baseline) or with the indicated inhibitors or their combination.

View larger version (15K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 5. Distal nephron net HCO3 reabsorption (Net JHCO3) and its components, HCO3 and H+ secretion, by in vivo microperfusion in controls without and with inhibitors after 3 wk. Positive/negative values indicate reabsorption/secretion, respectively.

View larger version (11K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 6. Distal nephron net HCO3 reabsorption (Net JHCO3) and its components, HCO3 and H+ secretion, by in vivo microperfusion in HiPro rats without and with bosentan after 3 wk. Positive/negative values indicate reabsorption/secretion, respectively. *P < 0.05 versus controls.

View larger version (10K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 7. Distal nephron net HCO3 reabsorption (Net JHCO3) and its components, HCO3 and H+ secretion, by in vivo microperfusion in HiPro rats without and with L-NAME after 3 wk. Positive/negative values indicate reabsorption/secretion, respectively. *P < 0.05 versus controls.

View larger version (12K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 8. Distal nephron net HCO3 reabsorption (Net JHCO3) and its components, HCO3 and H+ secretion, by in vivo microperfusion in HiPro+bosentan–treated rats without and with N-nitro-l-arginine methyl ester (L-NAME) after 3 wk. Positive/negative values indicate reabsorption/secretion, respectively. *P < 0.05 versus controls.

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion Conclusion References

Increased intake of dietary protein that is composed of acid-producing amino acids such as casein increases metabolic acid production and leads to increased renal acid excretion (18) that is mediated by augmented distal nephron acidification (1,2,19). Augmented distal nephron acidification is manifest by increased net HCO₃ reabsorption (20) that might be mediated by increased H⁺ secretion and/or reduced HCO₃ secretion (10). Increased H⁺ secretion enhances distal nephron acidification through reclaiming filtered HCO₃ and promoting NH₄⁺ secretion (21). In addition, increased distal nephron H⁺ secretion limits terminal nephron HCO₃ delivery that also promotes NH₄⁺ secretion (21) by permitting secreted H⁺ to titrate non-HCO₃ buffers, leading to net acid excretion rather than HCO₃ reclamation (22). Reduced distal nephron HCO₃ secretion also limits terminal nephron HCO₃ delivery with its attendant benefits to renal acidification. Both increased H⁺ secretion and decreased HCO₃ secretion mediate increased distal nephron acidification induced by dietary intake of mineral acids (23), and each component of enhanced distal nephron acidification in this model is endothelin mediated (24). Our previous investigations as to the mechanism(s) for HiPro-induced augmented distal nephron acidification revealed augmented distal nephron H⁺ secretion that is due to endothelin-stimulated increased Na⁺/H⁺ exchange and increased H⁺-ATPase activity (1,2), the latter as a result of endothelin-stimulated increased aldosterone activity (2). These studies further elucidate the cascade by which HiPro augments distal nephron acidification by showing that the previously demonstrated decrease in distal nephron HCO₃ secretion in HiPro rats (1,2) is mediated through increased NO that in turn is stimulated by endothelin. This increased distal nephron acidification limits the increased HCO₃ delivery to the terminal distal nephron that might otherwise occur in response to increased early distal HCO₃ delivery in situ (as a result of higher distal nephron fluid flows in HiPro rats as discussed in the Materials and Methods section) in HiPro rats compared with control animals (Table 3). Consequently, renal endothelins play an important mediating role in the increased H⁺ secretion/decreased HCO₃ secretion components of augmented distal nephron acidification that is induced by these two models of augmented distal nephron acidification, dietary intake of mineral acid and of acid-producing proteins.

The decreased distal nephron HCO₃ secretion that is induced by HiPro might help ameliorate the obligate HCO₃ secretion that occurs in response to increased fluid flows in this nephron segment (25) and thereby ameliorate the increased terminal HCO₃ delivery that might otherwise occur with the increased distal nephron fluid flows that are induced by HiPro (1). Decreased distal nephron HCO₃ secretion that is mediated by endothelins also seems to ameliorate the increase in terminal HCO₃ delivery in distal nephrons of remnant kidneys that might otherwise occur as a result of increased distal nephron fluid flows that also characterizes this setting (26). Together, the data suggest that increased NO action that is stimulated by endothelins limits HCO₃ secretion with its attendant decreased acidification that would otherwise occur in these two settings of increased distal nephron fluid flow (remnant kidneys and HiPro).

These studies support that NO enhances distal nephron acidification as supported by some (7) but not all (27) previous investigations. The latter study showed that NO donors inhibit distal nephron H⁺-ATPase activity and that this effect was prevented by NOS inhibition (27). Whether the differences between the latter and our studies are due to the probable supraphysiologic NO levels induced by NO donors, to the in vitro preparation used (compared with the in vivo preparation of our studies), or to other differences are not known. Our studies are consistent with the former studies, showing that NOS inhibition with L-NAME limits urine and distal nephron acidification in animals that are given an acid challenge. In the former studies, this acid challenge was provided by dietary NH₄Cl, whereas in these studies, the challenge was provided by increased ingestion of acid-producing protein (casein). The former and present studies support an important role of NO in mediating the augmented distal nephron acidification induced by a systemic acid challenge. These studies suggest that NO increases distal nephron acidification in this setting by reducing HCO₃ secretion in this nephron segment. Whether decreased distal nephron HCO₃ secretion that is mediated by NO in this setting is due to modulation of the actions of existing membrane transporters that secrete HCO₃ and/or by affecting the number and membrane location of these transporters was not determined. A chloride-bicarbonate exchanger in the brush border membrane of mammalian duodenal crypt cells mediates HCO₃ secretion by this intestinal segment (28), and NOS inhibition with L-NAME stimulates its activity (29). These data are consistent with NO-mediated inhibition of HCO₃ secretion in this epithelium. Increased NO activity that is induced by augmented endothelin activity might similarly inhibit chloride-bicarbonate exchange–mediated HCO₃ secretion in the mammalian distal nephron in response to increased dietary intake of acid-producing protein such as casein. This NO effect might be mediated directly or indirectly. Figure 9 shows a proposed cascade by which HiPro increases urine NAE that is supported by our series of studies to date.

View larger version (18K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 9. Proposed cascade for mechanisms by which HiPro increases renal acid excretion. NO, nitric oxide; NH4+, ammonium; H+, proton; H+ ATPase, proton ATPase.

	Conclusion

Top Abstract Introduction Materials and Methods Results Discussion Conclusion References

 
These studies show that HiPro as purified casein augments distal nephron acidification as a result in part of reduced HCO₃ secretion that is mediated by increased NO.

	Acknowledgments

 
This work was supported by funds from the Larry and Jane Woirhaye Memorial Endowment in Renal Research, the Texas Tech University Health Sciences Center.

We are grateful to Jeri Tasby, Cathy Hudson, and Callenda Hacker for expert technical assistance.

	Footnotes

 
Published online ahead of print. Publication date available at www.jasn.org.

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Top Abstract Introduction Materials and Methods Results Discussion Conclusion References

 

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This Article Abstract Full Text (PDF) All Versions of this Article: ASN.2005070775v1 17/2/406    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wesson, D. E. Articles by Prabhakar, S. Search for Related Content PubMed PubMed Citation Articles by Wesson, D. E. Articles by Prabhakar, S.