Meta-data analysis of kidney stone disease highlights ATP1A1 involvement in renal crystal formation
Nephrolithiasis is a complicated disease affected by various environmental and genetic factors. Crystal-cell adhesion is a critical initiation process during kidney stone formation. However, genes regulated by environmental and genetic factors in this process remain unclear. In the present study, we...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-05-01
|
| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231723000496 |
| _version_ | 1811154749979885568 |
|---|---|
| author | Yang Li Xiuli Lu Zhihao Yu Haozhen Wang Bing Gao |
| author_facet | Yang Li Xiuli Lu Zhihao Yu Haozhen Wang Bing Gao |
| author_sort | Yang Li |
| collection | DOAJ |
| description | Nephrolithiasis is a complicated disease affected by various environmental and genetic factors. Crystal-cell adhesion is a critical initiation process during kidney stone formation. However, genes regulated by environmental and genetic factors in this process remain unclear. In the present study, we integrated the gene expression profile data and the whole-exome sequencing data of patients with calcium stones, and found that ATP1A1 might be a key susceptibility gene involved in calcium stone formation. The study showed that the T-allele of rs11540947 in the 5′-untranslated region of ATP1A1 was associated with a higher risk of nephrolithiasis and lower activity of a promoter of ATP1A1. Calcium oxalate crystal deposition decreased ATP1A1 expression in vitro and in vivo and was accompanied by the activation of the ATP1A1/Src/ROS/p38/JNK/NF-κB signaling pathway. However, the overexpression of ATP1A1 or treatment with pNaKtide, a specific inhibitor of the ATP1A1/Src complex, inhibited the ATP1A1/Src signal system and alleviated oxidative stress, inflammatory responses, apoptosis, crystal-cell adhesion, and stone formation. Moreover, the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine reversed ATP1A1 down-regulation induced by crystal deposition. In conclusion, this is the first study to show that ATP1A1, a gene modulated by environmental factors and genetic variations, plays an important role in renal crystal formation, suggesting that ATP1A1 may be a potential therapeutic target for treating calcium stones. |
| first_indexed | 2024-04-10T04:22:18Z |
| format | Article |
| id | doaj.art-e825e9d9e05e4c08ba6e01fea9dd986a |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-10T04:22:18Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-e825e9d9e05e4c08ba6e01fea9dd986a2023-03-11T04:19:41ZengElsevierRedox Biology2213-23172023-05-0161102648Meta-data analysis of kidney stone disease highlights ATP1A1 involvement in renal crystal formationYang Li0Xiuli Lu1Zhihao Yu2Haozhen Wang3Bing Gao4Department of Biochemistry and Molecular Biology, Life Science School, Liaoning University, Shenyang, 110036, China; Department of Cell biology and Genetics, Shenyang Medical College, Shenyang 110034, ChinaDepartment of Biochemistry and Molecular Biology, Life Science School, Liaoning University, Shenyang, 110036, ChinaDepartment of Cell biology and Genetics, Shenyang Medical College, Shenyang 110034, ChinaDepartment of Biochemistry and Molecular Biology, Life Science School, Liaoning University, Shenyang, 110036, ChinaDepartment of Cell biology and Genetics, Shenyang Medical College, Shenyang 110034, China; Corresponding author. Department of Cell biology and Genetics, Shenyang Medical College, Huanghe North Street No.146, Shenyang, 110034, China.Nephrolithiasis is a complicated disease affected by various environmental and genetic factors. Crystal-cell adhesion is a critical initiation process during kidney stone formation. However, genes regulated by environmental and genetic factors in this process remain unclear. In the present study, we integrated the gene expression profile data and the whole-exome sequencing data of patients with calcium stones, and found that ATP1A1 might be a key susceptibility gene involved in calcium stone formation. The study showed that the T-allele of rs11540947 in the 5′-untranslated region of ATP1A1 was associated with a higher risk of nephrolithiasis and lower activity of a promoter of ATP1A1. Calcium oxalate crystal deposition decreased ATP1A1 expression in vitro and in vivo and was accompanied by the activation of the ATP1A1/Src/ROS/p38/JNK/NF-κB signaling pathway. However, the overexpression of ATP1A1 or treatment with pNaKtide, a specific inhibitor of the ATP1A1/Src complex, inhibited the ATP1A1/Src signal system and alleviated oxidative stress, inflammatory responses, apoptosis, crystal-cell adhesion, and stone formation. Moreover, the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine reversed ATP1A1 down-regulation induced by crystal deposition. In conclusion, this is the first study to show that ATP1A1, a gene modulated by environmental factors and genetic variations, plays an important role in renal crystal formation, suggesting that ATP1A1 may be a potential therapeutic target for treating calcium stones.http://www.sciencedirect.com/science/article/pii/S2213231723000496NephrolithiasisGene expressionOxidative stressDNA methylation |
| spellingShingle | Yang Li Xiuli Lu Zhihao Yu Haozhen Wang Bing Gao Meta-data analysis of kidney stone disease highlights ATP1A1 involvement in renal crystal formation Redox Biology Nephrolithiasis Gene expression Oxidative stress DNA methylation |
| title | Meta-data analysis of kidney stone disease highlights ATP1A1 involvement in renal crystal formation |
| title_full | Meta-data analysis of kidney stone disease highlights ATP1A1 involvement in renal crystal formation |
| title_fullStr | Meta-data analysis of kidney stone disease highlights ATP1A1 involvement in renal crystal formation |
| title_full_unstemmed | Meta-data analysis of kidney stone disease highlights ATP1A1 involvement in renal crystal formation |
| title_short | Meta-data analysis of kidney stone disease highlights ATP1A1 involvement in renal crystal formation |
| title_sort | meta data analysis of kidney stone disease highlights atp1a1 involvement in renal crystal formation |
| topic | Nephrolithiasis Gene expression Oxidative stress DNA methylation |
| url | http://www.sciencedirect.com/science/article/pii/S2213231723000496 |
| work_keys_str_mv | AT yangli metadataanalysisofkidneystonediseasehighlightsatp1a1involvementinrenalcrystalformation AT xiulilu metadataanalysisofkidneystonediseasehighlightsatp1a1involvementinrenalcrystalformation AT zhihaoyu metadataanalysisofkidneystonediseasehighlightsatp1a1involvementinrenalcrystalformation AT haozhenwang metadataanalysisofkidneystonediseasehighlightsatp1a1involvementinrenalcrystalformation AT binggao metadataanalysisofkidneystonediseasehighlightsatp1a1involvementinrenalcrystalformation |