Unfavorable Reduction in the Ratio of Endothelin B to A Receptors in Experimental 5/6 Nephrectomy and Adenine Models of Chronic Renal Insufficiency
Abstract
:1. Introduction
2. Results
2.1. Twelve-Weeks of Chronic Renal Insufficiency Induced by 5/6 Nephrectomy
2.2. Twenty-Seven Weeks of Chronic Renal Insufficiency Induced by 5/6 Nephrectomy
2.3. Twelve Weeks of Chronic Renal Insufficiency Induced by 0.3% Adenine Diet
3. Discussion
4. Materials and Methods
4.1. Animals and Experimental Design
4.1.1. Twelve-Week 5/6 Nephrectomy Model with Oxonic Acid Diet Modulation
4.1.2. Twenty-Seven-Week 5/6 Nephrectomy Model with Calcium and Phosphate Diets and Intraperitoneal Paricacitol Injections
4.1.3. Twelve-Week Adenine Model with Endothelin a Receptor Antagonist and Calcimimetic
4.2. Plasma and Urine Determinations
4.3. Real-Time Quantitative RT-PCR
4.4. Kidney Autoradiography
4.5. ELISA
4.6. Tubulointerstitial Kidney Histology
4.7. Data Presentation and Analysis of Results
Author Contributions
Funding
Conflicts of Interest
References
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Sham | Sham+Oxo | NX | NX + Oxo | Two-Way ANOVA p-Values | |||
---|---|---|---|---|---|---|---|
NX | Oxo | Interaction NX*Oxo | |||||
Number of animals | 12 | 12 | 12 | 12 | |||
Body weight (g) week 9 | 433 ± 8 | 412 ± 11 | 448 ± 10 | 411 ± 8 | 0.441 | 0.004 | 0.377 |
Systolic blood pressure mmHg week 9 | 134 ± 7 | 136 ± 5 | 142 ± 6 | 152 ± 4 | 0.041 | 0.290 | 0.498 |
Creatinineclearance (mL/min) | 2.89 ± 0.36 | 1.99 ± 0.16 | 1.21 ± 0.06* | 1.19 ± 0.09 † | ND | ND | ND |
Plasma determinations | (n = 9) | (n = 12) | (n = 11) | (n= 12) | |||
Creatinine (µmol/L) | 40.2 ± 5.1 | 48.5 ± 3.0 | 81.9 ± 3.1 | 83.1 ± 8.1 | <0.001 | 0.204 | 0.128 |
Urea (mmol/L) | 6.6 ± 0.3 | 8.3 ± 0.4 | 13.5 ± 0.9 | 14.5 ± 2.0 | <0.001 | 0.099 | 0.171 |
Uric acid (µmol/L) | 36.0 ± 10.7 | 117.3 ± 20.9 * | 62.9 ± 19.0 | 152.3 ± 19.0 # | ND | ND | ND |
Calcium (mmol/L) | 2.42 ± 0.02 | 2.36 ± 0.02 | 2.43 ± 0.04 | 2.42 ± 0.02 | 0.280 | 0.235 | 0.399 |
Phosphate (mmol/L) | 1.38 ± 0.07 | 1.51 ± 0.06 | 1.88 ± 0.17 | 1.92 ± 0.18 | 0.002 | 0.427 | 0.618 |
Urine protein (mg/24 h) | 70.5 ± 10.1 | 44.0 ± 8.6 | 323.2 ± 31.6 | 247.0 ± 44.0 | <0.001 | 0.006 | 0.616 |
Tubulointerstitial damage index | 0.0 ± 0.0 | 0.0 ± 0.0 | 2.3 ± 0.4* | 0.7 ± 0.3†# | ND | ND | ND |
Kidney Endothelin receptors | |||||||
ETB mRNA copies × 103/ng total RNA | 4.02 ± 0.29 | 2.61 ± 0.39 | 0.97 ± 0.15 | 0.90 ± 0.13 | <0.001 | 0.037 | 0.085 |
ETA mRNA copies × 102/ng total RNA | 2.49 ± 0.26 | 1.72 ± 0.26 | 0.70 ± 0.14 | 0.81 ± 0.18 | <0.001 | 0.281 | 0.159 |
ETB vs. ETA mRNA | 17.2 ± 1.1 | 16.7 ± 1.4 | 15.4 ± 1.6 | 15.7 ± 2.8 | 0.156 | 0.474 | 0.786 |
Sham | NX | NX+Ca | NX+Pi | NX+Pari | |
---|---|---|---|---|---|
Number of animals | 13 | 7 | 11 | 7 | 9 |
Body weight (g) | 565 ± 8 | 507 ± 41 | 481 ± 15 | 431 ± 38 | 503 ± 32 |
Systolic blood pressure mmHg | 130 ± 2 | 171 ± 5 * | 143 ± 4 # | 161 ± 4 | 167 ± 5 |
Creatinineclearance (mL/min) | 1.84 ± 0.11 | 0.85 ± 0.17 * | 0.84 ± 0.07 | 0.69 ± 0.18 | 0.71 ± 0.15 |
Plasma determinations | |||||
Creatinine (µmol/L) | 66.6 ± 2.2 | 170.0 ± 37.7 * | 116.5 ± 7.3 | 178.0 ± 30.9 | 209.0 ± 41.7 |
Urea (mmol/L) | 5.3 ± 0.2 | 23.3 ± 8.7 * | 12.9 ± 1.1 | 34.9 ± 11.5 | 33.8 ± 9.8 |
25OH-D3 (nmol/L) | 33.4 ± 2.8 | 19.8 ± 4.0 * | 13.8 ± 0.9 | 16.0 ± 1.3 | 13.0 ± 0.9 |
1,25(OH)2D3 (pmol/L) | 273.0 ± 27.8 | 70.5 ± 22.9 * | 105.8 ± 22.0 | 105.5 ± 42.9 | 6.2 ± 1.2# |
Ionized calcium (mmol/L) | 1.35 ± 0.01 | 1.34 ± 0.03 | 1.59 ± 0.04 # | 0.93 ± 0.09 # | 1.31 ± 0.05 |
Phosphate (mmol/L) | 1.19 ± 0.05 | 2.52 ± 0.54 * | 0.70 ± 0.06 # | 5.47 ± 1.21 | 3.03 ± 0.43 |
PTH (pg/mL) | 102.4 ± 52.7 | 1172.8 ± 369.8 * | 3.7 ± 0.5 # | 3619.7 ± 255.0 # | 618.9 ± 253.8 |
Urine protein (mg/24 h) | 132.7 ± 21.0 | 359.1 ± 49.6 * | 522.5 ± 50.6 | 626.8 ± 39.5 # | 432.5 ± 56.6 |
Tubulointerstitial damage index | 0.6 ± 0.1 | 2.9 ± 0.3 * | 1.9 ± 0.1# | 3.2 ± 0.3 | 3.5 ± 0.3 |
Kidney Endothelin receptors | |||||
ETB mRNA copies × 104/ng total RNA | 0.84 ± 0.07 | 1.41 ± 0.10 * | 1.52 ± 0.07 | 1.23 ± 0.10 | 1.28 ± 0.06 |
ETA mRNA copies × 103/ng total RNA | 0.93 ± 0.08 | 2.43 ± 0.39 * | 2.12 ± 0.11 | 2.38 ± 0.29 | 1.85 ± 0.19 |
ETB vs. ETA mRNA | 9.9 ± 1.4 | 6.7 ± 1.4 | 7.5 ± 0.8 | 5.7 ± 1.0 | 8.3 ± 2.0 |
Control | Ade | Ade+S | Ade+C | Ade+SC | Adenine Groups Two-Way ANOVA p-Values | |||
---|---|---|---|---|---|---|---|---|
Sita | Cina | Interaction Sita*Cina | ||||||
Number of animals | 12 | 20 | 16 | 16 | 16 | |||
Body weight (g) | ||||||||
week 12 | 450 ± 11 | 339 ± 6 * | 341 ± 6 | 340 ± 7 | 359 ± 8 | 0.136 | 0.160 | 0.253 |
Systolic Blood Pressure (mmHg) | ||||||||
week 9 | 137 ± 2 | 138 ± 1 | 130 ± 2 † | 138 ± 1 ‡ | 129 ± 2 | <0.001 | 0.624 | 0.722 |
Creatinine clearance (mL/min) | 1.70 ± 0.12 | 0.28 ± 0.02 * | 0.41 ± 0.03 † | 0.33 ± 0.04 | 0.44 ± 0.05 | <0.001 | 0.494 | 0.743 |
Plasma determinations | ||||||||
Creatinine (µmol/l) | 61.3 ± 4.0 | 212.6 ± 9.0 * | 160.2 ± 9.2 † | 202.4 ± 16.6 | 154.2 ± 10.2 | <0.001 | 0.309 | 0.794 |
Urea (mmol/L) | 9.0 ± 0.4 | 40.8 ± 1.4 * | 32.5 ± 1.3 † | 39.8 ± 2.2 | 30.8 ± 1.8 | <0.001 | 0.270 | 0.728 |
Uric acid (µmol/l) | 93.8 ± 12.0 | 30.1 ± 4.6 * | 18.6 ± 1.4 † | 31.7 ± 4.5 ‡ | 18.0 ± 1.5 | <0.001 | 0.915 | 0.650 |
Calcium (mmol/L) | 2.31 ± 0.02 | 2.27 ± 0.05 | 2.37 ± 0.12 ‡ | 2.20 ± 0.03 | 2.10 ± 0.03 | ND | ND | ND |
Phosphate (mmol/L) | 1.10 ± 0.09 | 1.83 ± 0.09 * | 1.53 ± 0.08 ‡ | 1.95 ± 0.12 | 2.06 ± 0.08 | ND | ND | ND |
PTH (pg/mL) | 31.6 ± 6.6 | 558.2 ± 51.2 * | 324.7 ± 63.1 †,‡ | 89.6 ± 28.2 † | 47.9 ± 9.4 | ND | ND | ND |
Urine protein (mg/24 h) | 14.7 ± 1.1 | 13.9 ± 1.7 | 11.2 ± 1.1 | 12.5 ± 2.6 | 11.7 ± 1.4 | 0.710 | 0.522 | 0.416 |
Kidney Endothelin receptors | ||||||||
ETB mRNA copies × 104/ng total RNA | 2.69 ± 0.17 | 1.70 ± 0.10 * | 1.37 ± 0.12 | 1.67 ± 0.13 | 1.51 ± 0.10 | ND | ND | ND |
ETA mRNA copies × 103/ng total RNA | 1.22 ± 0.13 | 5.78 ± 0.34 * | 5.41 ± 0.51 | 5.50 ± 0.43 | 4.47 ± 0.34 | 0.090 | 0.137 | 0.417 |
ETB vs. ETA mRNA | 23.8 ± 1.9 | 3.0 ± 0.2 * | 2.6 ± 0.2 | 3.1 ± 0.2 | 3.7 ± 0.4 | 0.715 | 0.034 | 0.080 |
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Törmänen, S.; Lakkisto, P.; Eräranta, A.; Kööbi, P.; Tikkanen, I.; Niemelä, O.; Mustonen, J.; Pörsti, I. Unfavorable Reduction in the Ratio of Endothelin B to A Receptors in Experimental 5/6 Nephrectomy and Adenine Models of Chronic Renal Insufficiency. Int. J. Mol. Sci. 2020, 21, 936. https://doi.org/10.3390/ijms21030936
Törmänen S, Lakkisto P, Eräranta A, Kööbi P, Tikkanen I, Niemelä O, Mustonen J, Pörsti I. Unfavorable Reduction in the Ratio of Endothelin B to A Receptors in Experimental 5/6 Nephrectomy and Adenine Models of Chronic Renal Insufficiency. International Journal of Molecular Sciences. 2020; 21(3):936. https://doi.org/10.3390/ijms21030936
Chicago/Turabian StyleTörmänen, Suvi, Päivi Lakkisto, Arttu Eräranta, Peeter Kööbi, Ilkka Tikkanen, Onni Niemelä, Jukka Mustonen, and Ilkka Pörsti. 2020. "Unfavorable Reduction in the Ratio of Endothelin B to A Receptors in Experimental 5/6 Nephrectomy and Adenine Models of Chronic Renal Insufficiency" International Journal of Molecular Sciences 21, no. 3: 936. https://doi.org/10.3390/ijms21030936