Effects of Cacna1d D307G Mutation on Blood Pressure and Kidney Function in Rats with Salt Loading
Introduction: Our recent findings revealed that CACNA1D D307G mutation participates in the early-onset hypertension. Methods: We used the CRISPR/Cas9 technique to generate the Cacna1d D307G mutation rat model and investigated the effects of Cacna1d D307G mutation on blood pressure (BP) an...
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Karger Publishers
2025-01-01
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| Series: | Kidney & Blood Pressure Research |
| Online Access: | https://karger.com/article/doi/10.1159/000542828 |
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| author | Lan Cheng Hui Chen R. Nfornah Maboh Huan Wang |
| author_facet | Lan Cheng Hui Chen R. Nfornah Maboh Huan Wang |
| author_sort | Lan Cheng |
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Introduction: Our recent findings revealed that CACNA1D D307G mutation participates in the early-onset hypertension. Methods: We used the CRISPR/Cas9 technique to generate the Cacna1d D307G mutation rat model and investigated the effects of Cacna1d D307G mutation on blood pressure (BP) and renal function. Rats fed normal-salt diet had normal plasma aldosterone levels but higher plasma ET-1 and mildly elevated systolic BP (SBP) in D307G and G307G rats compared with the wild type (WT) until 24 weeks. Renal function and renal histopathology did not significantly differ among the three groups. Results: When fed high-salt diet (HSD), D307G and G307G rats showed more sensitivity to HSD. The results showed a further increase in SBP than in WT rats. Plasma and vascular endothelin-1 (ET-1) level and cortex and renal artery endothelin type A (ETA) receptor protein expression were significantly increased. Enhanced renal injury was also noted as indicated by an increased ratio of kidney weight/body weight, elevated urinary protein and albumin/creatinine ratio, higher kidney injury molecule-1 (KIM-1) levels, advanced fibrosis and apoptosis, and inflammation. Further experiments revealed a reduction in urinary sodium excretion and creatinine clearance. Higher protein expression of renal cortex epithelial sodium channel α subunit (αENaC) was confirmed in D307G and G307G rats fed HSD. However, a selective ETA receptor blockade (ABT-627) could partially reverse the increased SBP, increased serum KIM-1 level, upregulated renal cortex protein expression of αENaC, and reduced urinary sodium excretion with reduced creatinine clearance in D307G rats fed HSD. Conclusion: Activation of the ET-1/ETA system in D307G mutation rats might have contributed to increased sensitivity to salt loading, augmented hypertension, and exacerbated the renal injury. |
| format | Article |
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| institution | DOAJ |
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| language | English |
| publishDate | 2025-01-01 |
| publisher | Karger Publishers |
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| series | Kidney & Blood Pressure Research |
| spelling | doaj-art-df4e2e1afdd04398871dfe7aad7196ad2025-08-20T03:09:47ZengKarger PublishersKidney & Blood Pressure Research1423-01432025-01-01501466010.1159/000542828Effects of Cacna1d D307G Mutation on Blood Pressure and Kidney Function in Rats with Salt LoadingLan ChengHui ChenR. Nfornah MabohHuan Wang Introduction: Our recent findings revealed that CACNA1D D307G mutation participates in the early-onset hypertension. Methods: We used the CRISPR/Cas9 technique to generate the Cacna1d D307G mutation rat model and investigated the effects of Cacna1d D307G mutation on blood pressure (BP) and renal function. Rats fed normal-salt diet had normal plasma aldosterone levels but higher plasma ET-1 and mildly elevated systolic BP (SBP) in D307G and G307G rats compared with the wild type (WT) until 24 weeks. Renal function and renal histopathology did not significantly differ among the three groups. Results: When fed high-salt diet (HSD), D307G and G307G rats showed more sensitivity to HSD. The results showed a further increase in SBP than in WT rats. Plasma and vascular endothelin-1 (ET-1) level and cortex and renal artery endothelin type A (ETA) receptor protein expression were significantly increased. Enhanced renal injury was also noted as indicated by an increased ratio of kidney weight/body weight, elevated urinary protein and albumin/creatinine ratio, higher kidney injury molecule-1 (KIM-1) levels, advanced fibrosis and apoptosis, and inflammation. Further experiments revealed a reduction in urinary sodium excretion and creatinine clearance. Higher protein expression of renal cortex epithelial sodium channel α subunit (αENaC) was confirmed in D307G and G307G rats fed HSD. However, a selective ETA receptor blockade (ABT-627) could partially reverse the increased SBP, increased serum KIM-1 level, upregulated renal cortex protein expression of αENaC, and reduced urinary sodium excretion with reduced creatinine clearance in D307G rats fed HSD. Conclusion: Activation of the ET-1/ETA system in D307G mutation rats might have contributed to increased sensitivity to salt loading, augmented hypertension, and exacerbated the renal injury. https://karger.com/article/doi/10.1159/000542828 |
| spellingShingle | Lan Cheng Hui Chen R. Nfornah Maboh Huan Wang Effects of Cacna1d D307G Mutation on Blood Pressure and Kidney Function in Rats with Salt Loading Kidney & Blood Pressure Research |
| title | Effects of Cacna1d D307G Mutation on Blood Pressure and Kidney Function in Rats with Salt Loading |
| title_full | Effects of Cacna1d D307G Mutation on Blood Pressure and Kidney Function in Rats with Salt Loading |
| title_fullStr | Effects of Cacna1d D307G Mutation on Blood Pressure and Kidney Function in Rats with Salt Loading |
| title_full_unstemmed | Effects of Cacna1d D307G Mutation on Blood Pressure and Kidney Function in Rats with Salt Loading |
| title_short | Effects of Cacna1d D307G Mutation on Blood Pressure and Kidney Function in Rats with Salt Loading |
| title_sort | effects of cacna1d d307g mutation on blood pressure and kidney function in rats with salt loading |
| url | https://karger.com/article/doi/10.1159/000542828 |
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