TRPV1 Hyperfunction Involved in Uremic Toxin Indoxyl Sulfate-Mediated Renal Tubular Damage
Indoxyl sulfate (IS) is accumulated during severe renal insufficiency and known for its nephrotoxic properties. Transient receptor potential vanilloid 1 (TRPV1) is present in the kidney and acts as a renal sensor. However, the mechanism underlying IS-mediated renal tubular damage in view of TRPV1 is...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-08-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/17/6212 |
| _version_ | 1797555353317015552 |
|---|---|
| author | Chien-Lin Lu Chun-Hou Liao Kuo-Cheng Lu Ming-Chieh Ma |
| author_facet | Chien-Lin Lu Chun-Hou Liao Kuo-Cheng Lu Ming-Chieh Ma |
| author_sort | Chien-Lin Lu |
| collection | DOAJ |
| description | Indoxyl sulfate (IS) is accumulated during severe renal insufficiency and known for its nephrotoxic properties. Transient receptor potential vanilloid 1 (TRPV1) is present in the kidney and acts as a renal sensor. However, the mechanism underlying IS-mediated renal tubular damage in view of TRPV1 is lacking. Here, we demonstrated that TRPV1 was expressed in tubular cells of Lilly Laboratories cell-porcine kidney 1 (LLC-PK<sub>1</sub>) and Madin-Darby canine kidney cells (MDCK). IS treatment in both cells exhibited tubular damage with increased LDH release and reduced cell viability in dose- and time-dependent manners. MDCK, however, was more vulnerable to IS. We, therefore, investigated MDCK cells to explore a more detailed mechanism. Interestingly, IS-induced tubular damage was markedly attenuated in the presence of selective TRPV1 blockers. IS showed no effect on TRPV1 expression but significantly increased arachidonate 12-lipoxygenase (ALOX12) protein, mRNA expression, and 12(<i>S</i>)-hydroxyeicosatetraenoic acid (12(<i>S</i>)-HETE) amounts in a dose-dependent manner, indicating that the ALOX12/12(<i>S</i>)-HETE pathway induced TRPV1 hyperfunction in IS-mediated tubulotoxicity. Blockade of ALOX12 by cinnamyl-3,4-dihydroxy-α-cyanocinnamate or baicalein attenuated the effects of IS. Since aryl hydrocarbon receptor (AhR) activation after IS binding is crucial in mediating cell death, here, we found that the AhR blockade not only ameliorated tubular damage but also attenuated ALOX12 expression and 12(<i>S</i>)-HETE production caused by IS. The uremic toxic adsorbent AST-120, however, showed little effect on ALOX12 and 12(<i>S</i>)-HETE, as well as IS-induced cell damage. These results clearly indicated that IS activated AhR and then upregulated ALOX12, and this induced endovanilloid 12(<i>S</i>)-HETE synthesis and contributed to TRPV1 hyperfunction in IS-treated tubular cells. Further study on TRPV1 may attenuate kidney susceptibility to the functional loss of end-stage kidney disease via IS. |
| first_indexed | 2024-03-10T16:46:14Z |
| format | Article |
| id | doaj.art-d297f3acf12c4532b10f0794daa9967c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T16:46:14Z |
| publishDate | 2020-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d297f3acf12c4532b10f0794daa9967c2023-11-20T11:39:06ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-08-012117621210.3390/ijms21176212TRPV1 Hyperfunction Involved in Uremic Toxin Indoxyl Sulfate-Mediated Renal Tubular DamageChien-Lin Lu0Chun-Hou Liao1Kuo-Cheng Lu2Ming-Chieh Ma3Division of Nephrology, Department of Medicine, Fu Jen Catholic University Hospital, New Taipei City 24205, TaiwanSchool of Medicine, Fu Jen Catholic University, New Taipei City 24205, TaiwanDivision of Nephrology, Department of Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, TaiwanSchool of Medicine, Fu Jen Catholic University, New Taipei City 24205, TaiwanIndoxyl sulfate (IS) is accumulated during severe renal insufficiency and known for its nephrotoxic properties. Transient receptor potential vanilloid 1 (TRPV1) is present in the kidney and acts as a renal sensor. However, the mechanism underlying IS-mediated renal tubular damage in view of TRPV1 is lacking. Here, we demonstrated that TRPV1 was expressed in tubular cells of Lilly Laboratories cell-porcine kidney 1 (LLC-PK<sub>1</sub>) and Madin-Darby canine kidney cells (MDCK). IS treatment in both cells exhibited tubular damage with increased LDH release and reduced cell viability in dose- and time-dependent manners. MDCK, however, was more vulnerable to IS. We, therefore, investigated MDCK cells to explore a more detailed mechanism. Interestingly, IS-induced tubular damage was markedly attenuated in the presence of selective TRPV1 blockers. IS showed no effect on TRPV1 expression but significantly increased arachidonate 12-lipoxygenase (ALOX12) protein, mRNA expression, and 12(<i>S</i>)-hydroxyeicosatetraenoic acid (12(<i>S</i>)-HETE) amounts in a dose-dependent manner, indicating that the ALOX12/12(<i>S</i>)-HETE pathway induced TRPV1 hyperfunction in IS-mediated tubulotoxicity. Blockade of ALOX12 by cinnamyl-3,4-dihydroxy-α-cyanocinnamate or baicalein attenuated the effects of IS. Since aryl hydrocarbon receptor (AhR) activation after IS binding is crucial in mediating cell death, here, we found that the AhR blockade not only ameliorated tubular damage but also attenuated ALOX12 expression and 12(<i>S</i>)-HETE production caused by IS. The uremic toxic adsorbent AST-120, however, showed little effect on ALOX12 and 12(<i>S</i>)-HETE, as well as IS-induced cell damage. These results clearly indicated that IS activated AhR and then upregulated ALOX12, and this induced endovanilloid 12(<i>S</i>)-HETE synthesis and contributed to TRPV1 hyperfunction in IS-treated tubular cells. Further study on TRPV1 may attenuate kidney susceptibility to the functional loss of end-stage kidney disease via IS.https://www.mdpi.com/1422-0067/21/17/6212transient receptor potential vanilloid 1indoxyl sulfatearyl hydrocarbon receptorarachidonate 12-lipoxygenase12(<i>S</i>)-hydroxyeicosatetraenoic acidrenal tubular damage |
| spellingShingle | Chien-Lin Lu Chun-Hou Liao Kuo-Cheng Lu Ming-Chieh Ma TRPV1 Hyperfunction Involved in Uremic Toxin Indoxyl Sulfate-Mediated Renal Tubular Damage International Journal of Molecular Sciences transient receptor potential vanilloid 1 indoxyl sulfate aryl hydrocarbon receptor arachidonate 12-lipoxygenase 12(<i>S</i>)-hydroxyeicosatetraenoic acid renal tubular damage |
| title | TRPV1 Hyperfunction Involved in Uremic Toxin Indoxyl Sulfate-Mediated Renal Tubular Damage |
| title_full | TRPV1 Hyperfunction Involved in Uremic Toxin Indoxyl Sulfate-Mediated Renal Tubular Damage |
| title_fullStr | TRPV1 Hyperfunction Involved in Uremic Toxin Indoxyl Sulfate-Mediated Renal Tubular Damage |
| title_full_unstemmed | TRPV1 Hyperfunction Involved in Uremic Toxin Indoxyl Sulfate-Mediated Renal Tubular Damage |
| title_short | TRPV1 Hyperfunction Involved in Uremic Toxin Indoxyl Sulfate-Mediated Renal Tubular Damage |
| title_sort | trpv1 hyperfunction involved in uremic toxin indoxyl sulfate mediated renal tubular damage |
| topic | transient receptor potential vanilloid 1 indoxyl sulfate aryl hydrocarbon receptor arachidonate 12-lipoxygenase 12(<i>S</i>)-hydroxyeicosatetraenoic acid renal tubular damage |
| url | https://www.mdpi.com/1422-0067/21/17/6212 |
| work_keys_str_mv | AT chienlinlu trpv1hyperfunctioninvolvedinuremictoxinindoxylsulfatemediatedrenaltubulardamage AT chunhouliao trpv1hyperfunctioninvolvedinuremictoxinindoxylsulfatemediatedrenaltubulardamage AT kuochenglu trpv1hyperfunctioninvolvedinuremictoxinindoxylsulfatemediatedrenaltubulardamage AT mingchiehma trpv1hyperfunctioninvolvedinuremictoxinindoxylsulfatemediatedrenaltubulardamage |