Regulation of Rhcg, an ammonia transporter, by aldosterone in the kidney

in Journal of Endocrinology
Authors:
Koji Eguchi Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Chuo-ku, Kumamoto, Japan

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Yuichiro Izumi Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Chuo-ku, Kumamoto, Japan

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https://orcid.org/0000-0003-0827-9619
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Yukiko Yasuoka Department of Physiology, Kitasato University School of Medicine, Minami-ku, Sagamihara, Kanagawa, Japan

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Terumasa Nakagawa Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Chuo-ku, Kumamoto, Japan

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Makoto Ono Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Chuo-ku, Kumamoto, Japan

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Kosuke Maruyama Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Chuo-ku, Kumamoto, Japan

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Naomi Matsuo Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Chuo-ku, Kumamoto, Japan

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Akiko Hiramatsu Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Chuo-ku, Kumamoto, Japan

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Hideki Inoue Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Chuo-ku, Kumamoto, Japan

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Yushi Nakayama Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Chuo-ku, Kumamoto, Japan

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Hiroshi Nonoguchi Division of Internal Medicine, Kitasato University Medical Center, Kitamoto, Saitama, Japan

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Hyun-Wook Lee Division of Nephrology, Hypertension, and Transplantation, University of Florida College of Medicine, Gainesville, Florida, USA

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I David Weiner Division of Nephrology, Hypertension, and Transplantation, University of Florida College of Medicine, Gainesville, Florida, USA
Nephrology and Hypertension Section, North Florida/South Georgia Veterans Health System, Gainesville, Florida, USA

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Yutaka Kakizoe Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Chuo-ku, Kumamoto, Japan

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Takashige Kuwabara Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Chuo-ku, Kumamoto, Japan

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Masashi Mukoyama Department of Nephrology, Kumamoto University Graduate School of Medical Sciences, Chuo-ku, Kumamoto, Japan

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Correspondence should be addressed to Y Izumi: izumi_yu@kumamoto-u.ac.jp
DOI:
https://doi.org/10.1530/JOE-20-0267
Volume/Issue:
Volume 249: Issue 2
Article Type:
Research Article
Page Range:
95–112
Online Publication Date:
May 2021
Copyright:
© 2021 Society for Endocrinology 2021
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Rhesus C glycoprotein (Rhcg), an ammonia transporter, is a key molecule in urinary acid excretion and is expressed mainly in the intercalated cells (ICs) of the renal collecting duct. In the present study we investigated the role of aldosterone in the regulation of Rhcg expression. In in vivo experiments using C57BL/6J mice, Western blot analysis showed that continuous subcutaneous administration of aldosterone increased the expression of Rhcg in membrane fraction of the kidney. Supplementation of potassium inhibited the effect of aldosterone on the Rhcg. Next, mice were subjected to adrenalectomy with or without administration of aldosterone, and then ad libitum 0.14 M NH4Cl containing water was given. NH4Cl load increased the expression of Rhcg in membrane fraction. Adrenalectomy decreased NH4Cl-induced Rhcg expression, which was restored by administration of aldosterone. Immunohistochemical studies revealed that NH4Cl load induced the localization of Rhcg at the apical membrane of ICs in the outer medullary collecting duct. Adrenalectomy decreased NH4Cl-induced membrane localization of Rhcg, which was restored by administration of aldosterone. For in vitro experiments, IN-IC cells, an immortalized cell line stably expressing Flag-tagged Rhcg (Rhcg-Flag), were used. Western blot analysis showed that aldosterone increased the expression of Rhcg-Flag in membrane fraction, while the increase in extracellular potassium level inhibited the effect of aldosterone. Both spironolactone and Gӧ6983, a PKC inhibitor, inhibited the expression of Rhcg-Flag in the membrane fraction. These results suggest that aldosterone regulates the membrane expression of Rhcg through the mineralocorticoid receptor and PKC pathways, which is modulated by extracellular potassium level.

Supplementary Materials

    • Supplemental table 1. Information of antibodies.
    • Supplemental Figure 1. Experimental design to examine the effect of aldosterone on urinary acid excretion and Rhcg expression. Mice were continuously administered aldosterone (10 µg/mouse/day) or vehicle using an osmotic minipump for three days. The minipump was subcutaneously implanted on the back under anesthetized. On days 0, 2, and 3 after the administration of aldosterone, urine was collected in tubes containing mineral oil for 24 h in a metabolic cage. Under anesthetization with 0.75 mg/kg medetomidine, 4.0 mg/kg midazolam, and 5.0 mg/kg butorphanol, arterial blood was taken from aorta and the kidneys were removed. Pieces of kidney tissue were immediately stored in 4% paraformaldehyde or designated reagents for further experiments.
    • Supplemental Figure 2. Experimental design to examine the role of aldosterone in urinary acid excretion and Rhcg expression under conditions of metabolic acidosis. Mice were subjected to bilateral adrenalectomy or sham operation and given free access to tap water containing 0.9% NaCl. After one week, mice were divided into the following four groups: 1) sham operation with vehicle (sham), 2) sham operation with vehicle under conditions of metabolic acidosis (sham-NH4Cl), 3) ADX with replacement of dexamethasone under conditions of metabolic acidosis (ADX-Dex-NH4Cl), and 4) ADX with replacement of dexamethasone and aldosterone under conditions of metabolic acidosis (ADX-Dex-Aldo-NH4Cl). Mice were continuously administered vehicle, dexamethasone (0.25 µg/mouse/day) or aldosterone (5 µg/mouse/day) via an osmotic minipump. On the following day, mice were given free access to tap water containing 0.9% NaCl or tap water containing 0.45% NaCl and 0.14 M NH4Cl for three days. On days 0, 2, 3, and 4 after osmotic minipump implantation, urine was collected in tubes containing mineral oil for 24 h in a metabolic cage. Under anesthetization with 0.75 mg/kg medetomidine, 4.0 mg/kg midazolam, and 5.0 mg/kg butorphanol, arterial blood was taken from aorta and the kidneys were removed. Pieces of kidney tissue were immediately stored in 4% paraformaldehyde/0.1M phosphate buffer or designated reagents for further experiments.
    • Supplemental Figure 3. Western blot of Rhcg protein in total tissue lysate and membrane fraction from the whole kidney. Specificity of the antibody against Rhcg was verified by Western blotting with 20 μg total tissue lysate and 10 μg membrane fraction from the whole kidney, showing a single thick band around 60 kDa.
    • Supplemental Figure 4. mRNA and protein expressions of Rhcg that were examined by real time PCR, Western blotting, and immunohistochemistry. A: mRNA expression of Rhcg in whole kidney tissue 3 days after administration of aldosterone. Aldosterone significantly but slightly increased Rhcg mRNA expression. The values for individual mice are shown together with a line and error bars representing the mean ± SEMs. n = 3 for the vehicle-treated and aldosterone-administered mice. B: Protein expression of Rhcg in total tissue lysate extracted from whole kidneys. Aldosterone significantly but slightly increased Rhcg expression. Representative Western blots are shown. The values for individual mice are shown together with a line and error bars representing the mean ± SEMs. n = 6 for the vehicle-treated and aldosterone-administered mice. C. Administration of aldosterone did not result in detectable changes in the intensity of Rhcg expression in the cortex, outer medulla, or inner medulla of the kidney.
    • Supplemental Figure 5. Rhcg protein expression in the kidney in a low-power micrograph under conditions of metabolic acidosis. In the cortex and inner medulla, NH4Cl loading, ADX, aldosterone replacement, or their combination caused no detectable changes in the Rhcg fluorescence intensity in the low-power micrograph. In the outer medulla, however, NH4Cl loading increased the Rhcg fluorescence intensity in sham-NH4Cl mice. ADX decreased the NH4Cl-induced fluorescence intensity in ADX-Dex-NH4Cl mice. Replacement of aldosterone tended to restore the fluorescence intensity in ADX-Dex-Aldo-NH4Cl mice.
    • Supplemental Figure 6. Effects of acid loading and ADX on the localization of the Rhcg protein in the CCD. Rhcg protein localization in the CCD in a high-power micrograph. The localization of Rhcg (red) was evaluated by immunohistochemistry. AQP2 protein expression (green) was examined to distinguish ICs from PCs. The Rhcg protein was expressed both in PCs and ICs. NH4Cl loading did not show ovious change in membrane localization of Rhcg in sham-NH4Cl mice. ADX inhibited and aldosterone replacement restored the localization of Rhcg at the basolateral membrane, respectively, in ADX-Dex-NH4Cl and ADX-Dex-Aldo-NH4Cl mice.
    • Supplemental Figure 7. mRNA and protein expression of Sgk1 and Rhcg in IN-IC cells with the treatment with aldosterone. A: Sgk1 mRNA expression in IN-IC cells transfected with pCMV mock vector. The expression of Sgk1 mRNA was increased by the treatment with aldosterone. Spironolactone inhibited the aldosterone-induced increase in Sgk1 expression. The values for individual samples are shown together with a line and error bars representing the mean &#x00B1; SEMs. n = 3. * P < 0.05. B: Sgk1 protein expression in IN-IC cells transfected with pCMV mock vector. Aldosterone increased Sgk1 protein expression in the whole-cell lysate. Spironolactone inhibited the aldosterone-induced increase in Sgk1 expression. The values for individual samples are shown together with a line and error bars representing the mean &#x00B1; SEMs. n = 3. * P < 0.05. C: Rhcg mRNA expression in IN-IC cells, transfected with pCMV mock vector. Aldosterone and spironolactone did not significantly change Rhcg mRNA expression. The values for individual samples are shown together with a line and error bars representing the mean &#x00B1; SEMs. n = 3. D: Western blot for the immunoprecipitation of Rhcg-Flag protein IN-IC cells. Lane 3 demonstrates a successful immunoprecipitation of Rhcg-Flag by anti-Flag antibody. Immunoprecipitation by mouse IgG (lane 1) with IN-IC cells expressing Rhcg-Flag and that by anti-Flag antibody with IN-IC cells transfected pCMV mock vector (lane 2) did not show Rhcg-Flag protein. E: Effects of aldosterone on the expression of Rhcg-Flag in whole cell lysate in the presence or the absence of MG132. Aldosterone did not change the expression of Rhcg-Flag in whole cell lysate regardless the presence of MG132.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2021 Society for Endocrinology 2021
Page(s):
18
Article Type:
Research Article
Received Date:
27 Feb 2021
Accepted Date:
09 Mar 2021
Print Publication Date:
01 May 2021
Online Publication Date:
May 2021
Keywords:
adrenal hormomes; ion channels; renal; physiology

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