Cisplatin Decreases ENaC Activity Contributing to Renal Salt Wasting Syndrome
Cisplatin (CDDP) is an important anticancer drug. A common side effect of CDDP is renal salt and water-wasting syndrome (RSWS). The origin of RSWS is obscure. Emerging evidence, though, suggests that broad inhibition of sodium transport proteins by CDDP may result in decreases in tubular reabsorptio...
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| Format: | Article |
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MDPI AG
2020-08-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/8/2140 |
| _version_ | 1797560529113317376 |
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| author | Antonio G. Soares Elena Mironova Crystal R. Archer Jorge Contreras James D. Stockand Tarek Mohamed Abd El-Aziz |
| author_facet | Antonio G. Soares Elena Mironova Crystal R. Archer Jorge Contreras James D. Stockand Tarek Mohamed Abd El-Aziz |
| author_sort | Antonio G. Soares |
| collection | DOAJ |
| description | Cisplatin (CDDP) is an important anticancer drug. A common side effect of CDDP is renal salt and water-wasting syndrome (RSWS). The origin of RSWS is obscure. Emerging evidence, though, suggests that broad inhibition of sodium transport proteins by CDDP may result in decreases in tubular reabsorption, causing increases in sodium and water excretion. In this sense, CDDP would be acting like a diuretic. The effect of CDDP on the epithelial Na<sup>+</sup> channel (ENaC), which is the final arbiter fine-tuning renal Na<sup>+</sup> excretion, is unknown. We test here whether CDDP affects ENaC to promote renal salt and water excretion. The effects of CDDP and benzamil (BZM), a blocker of ENaC, on excretion of a sodium load were quantified. Similar to BZM, CDDP facilitated renal Na<sup>+</sup> excretion. To directly quantify the effects on ENaC, principal cells in split-open tubules were patch clamped. CDDP, at doses comparable to those used for chemotherapy (1.5 µM), significantly decreased ENaC activity in native tubules. To further elaborate on this mechanism, the dose-dependent effects of CDDP on mouse ENaC (mENaC) heterologously expressed in Chinese Hamster Ovary (CHO) cells were tested using patch clamping. As in native tubules, CDDP significantly decreased the activity of mENaC expressed in CHO cells. Dose–response curves and competition with amiloride identified CDDP as a weak inhibitor of ENaC (apparent IC<sub>50</sub> = 1 µM) that competes with amiloride for inhibition of the channel, weakening the inhibitory actions of the latter. Such observations are consistent with CDDP being a partial modulator of ENaC, which possibly has a binding site that overlaps with that of amiloride. These findings are consistent with inhibition of ENaC by CDDP contributing to the RSWS caused by this important chemotherapy drug. |
| first_indexed | 2024-03-10T18:01:59Z |
| format | Article |
| id | doaj.art-3d9ea14f163b4da0a698ef8687782515 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T18:01:59Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-3d9ea14f163b4da0a698ef86877825152023-11-20T08:48:07ZengMDPI AGCancers2072-66942020-08-01128214010.3390/cancers12082140Cisplatin Decreases ENaC Activity Contributing to Renal Salt Wasting SyndromeAntonio G. Soares0Elena Mironova1Crystal R. Archer2Jorge Contreras3James D. Stockand4Tarek Mohamed Abd El-Aziz5Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229-3900, USADepartment of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229-3900, USADepartment of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229-3900, USADepartment of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229-3900, USADepartment of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229-3900, USADepartment of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229-3900, USACisplatin (CDDP) is an important anticancer drug. A common side effect of CDDP is renal salt and water-wasting syndrome (RSWS). The origin of RSWS is obscure. Emerging evidence, though, suggests that broad inhibition of sodium transport proteins by CDDP may result in decreases in tubular reabsorption, causing increases in sodium and water excretion. In this sense, CDDP would be acting like a diuretic. The effect of CDDP on the epithelial Na<sup>+</sup> channel (ENaC), which is the final arbiter fine-tuning renal Na<sup>+</sup> excretion, is unknown. We test here whether CDDP affects ENaC to promote renal salt and water excretion. The effects of CDDP and benzamil (BZM), a blocker of ENaC, on excretion of a sodium load were quantified. Similar to BZM, CDDP facilitated renal Na<sup>+</sup> excretion. To directly quantify the effects on ENaC, principal cells in split-open tubules were patch clamped. CDDP, at doses comparable to those used for chemotherapy (1.5 µM), significantly decreased ENaC activity in native tubules. To further elaborate on this mechanism, the dose-dependent effects of CDDP on mouse ENaC (mENaC) heterologously expressed in Chinese Hamster Ovary (CHO) cells were tested using patch clamping. As in native tubules, CDDP significantly decreased the activity of mENaC expressed in CHO cells. Dose–response curves and competition with amiloride identified CDDP as a weak inhibitor of ENaC (apparent IC<sub>50</sub> = 1 µM) that competes with amiloride for inhibition of the channel, weakening the inhibitory actions of the latter. Such observations are consistent with CDDP being a partial modulator of ENaC, which possibly has a binding site that overlaps with that of amiloride. These findings are consistent with inhibition of ENaC by CDDP contributing to the RSWS caused by this important chemotherapy drug.https://www.mdpi.com/2072-6694/12/8/2140Deg/ENaC channelsrenal sodium excretionhypertensiondiureticpseduohypoaldosteronismchemotherapy |
| spellingShingle | Antonio G. Soares Elena Mironova Crystal R. Archer Jorge Contreras James D. Stockand Tarek Mohamed Abd El-Aziz Cisplatin Decreases ENaC Activity Contributing to Renal Salt Wasting Syndrome Cancers Deg/ENaC channels renal sodium excretion hypertension diuretic pseduohypoaldosteronism chemotherapy |
| title | Cisplatin Decreases ENaC Activity Contributing to Renal Salt Wasting Syndrome |
| title_full | Cisplatin Decreases ENaC Activity Contributing to Renal Salt Wasting Syndrome |
| title_fullStr | Cisplatin Decreases ENaC Activity Contributing to Renal Salt Wasting Syndrome |
| title_full_unstemmed | Cisplatin Decreases ENaC Activity Contributing to Renal Salt Wasting Syndrome |
| title_short | Cisplatin Decreases ENaC Activity Contributing to Renal Salt Wasting Syndrome |
| title_sort | cisplatin decreases enac activity contributing to renal salt wasting syndrome |
| topic | Deg/ENaC channels renal sodium excretion hypertension diuretic pseduohypoaldosteronism chemotherapy |
| url | https://www.mdpi.com/2072-6694/12/8/2140 |
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