Col4a3-/- Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over-Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds
Abstract
:1. Introduction
2. Results
2.1. Different Genetic Background Affects Lifespan in Alport Mice
2.2. Echocardiography and Invasive Hemodynamics Revealed That Col4a3-/- 129x1/SvJ Mice Displayed More Impaired Systolic Function and More Diastolic Dysfunction When Compared to Balb/C and C57Bl/6
2.2.1. Systolic Function
2.2.2. Diastolic Function
2.2.3. Pulmonary Artery and Aorta Flow
2.2.4. Wall Thickness
2.2.5. Pressure-Volume (PV) Loop
2.3. Only Col4a3-/- 129x1/SvJ Mice Displayed Alteration in Blood Pressure by Tail Cuff
2.4. Respiratory Capacity Is Changed in Col4a3-/- on 129x1/SvJ, Col4a3-/- C57Bl/6 and Balb/C Backgrounds
2.4.1. Whole Body Plethysmography (WBP)
2.4.2. Diaphragm Ultrasonography and Gravimetry from the Lungs
2.5. Blood Urea Nitrogen (BUN) and Creatinine (CRE) Were Increased in Alport Mice Compared to WT Control Mice
2.6. Genetic Background Affects SGLT2 Expression in the Kidney
3. Discussion
4. Materials and Methods
4.1. Animals
4.2. Echocardiography, Strain Analysis and Diaphragm Ultrasonography
4.3. Tail-Cuff Blood Pressure Measurements
4.4. Whole Body Plethysmography for Assessment of Lung Function
4.5. Hemodynamics and Pressure-Volume Loops
4.6. Immunostaining, Imaging Acquisition and Analyses for SGLT-2 Quantification
4.7. Blood Urea Nitrogen (BUN),Creatinine (CRE) and Glucose (Glu) Quantification from the Plasma
4.8. Data Analyses and Statistics
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Echocardiography Parameters | 129J 8 Weeks Old | Balb/C 8 Weeks Old | C57Bl/6 20 Weeks Old | |||
---|---|---|---|---|---|---|
Systolic Function | ||||||
WT (n = 14) | Col4a3-/-(n = 15) | WT (n = 14) | Col4a3-/- (n = 10) | WT (n = 11) | Col4a3-/- (n = 10) | |
EF (%) | 56.74 ± 10.08 | 54.04 ± 15.97 | 48.02 ± 6.63 | 44.65 ± 11.61 | 58.97 ± 10.56 | 47.4 ± 8.8 |
SV (µL) | 38.4 ± 4.97 | 30.06 ± 6.74 * | 30.08 ± 6.05 †,€ | 27.85 ± 7.06 | 38.99 ± 5.83 | 37.5 ± 5.79 † |
CO (µL/min) | 15.55 ± 2.70 | 12.74 ± 2.58 †††† | 12.24 ± 3.06 | 12.06 ± 3.76 | 18.82 ± 4.32 | 16.1 ± 3.34 |
FS (%) | 29.77 ± 7.28 | 28.38 ± 10.93 | 23.91 ± 3.99 | 22.04 ± 6.46 | 30.12 ± 7.67 | 23.78 ± 5.41 |
ESV (µL) | 30.47 ± 9.53 | 27.92 ± 13.31 ¥ | 33.44 ± 6.85 | 35.23 ± 10.18 | 31.24 ± 15.11 | 42.36 ± 10.24 |
EDV (µL) | 68.88 ± 10.21 | 57.97 ± 12.45 ¥¥¥ | 62.64 ± 8.25 | 63.08 ± 7.93 † | 65.96 ± 9.77 | 79.86 ± 9.58 |
HR (bpm) | 413.54±40.29 ¥¥¥ | 424.94±40.05 | 412.78±44.68 †† | 447.71±42.53 | 495.34±48.61 | 446.64 ± 44.42 |
GLS (%) | −18.12 ± 4.04 | −12.85 ± 3.6 * | −14.9 ± 3.55 | −15.27 ± 4.4 | −16.62 ± 3.6 | −16.44 ± 2.12 |
GCS (%) | −19.22 ± 5.04 | −16.26 ± 5.04 | −14.89 ± 3.55 † | −15.91 ± 3.80 | −21.3 ± 6.45 | −17.52 ± 3.22 |
Diastolic function | ||||||
WT (n = 14) | Col4a3-/-(n = 15) | WT (n = 14) | Col4a3-/- (n = 10) | WT (n = 11) | Col4a3-/- (n = 10) | |
A′ velocity (mms/s) | −22.05 ± 5.14 | −18.38 ± 3.84 | −18.43 ± 5.60 | −16.9 ± 6.12 | −22.59 ± 7.4 | −16.47 ± 3.15 |
E′ velocity (mm/s) | −21.25 ± 5.73 | −15.91 ± 4.16 | −20.99 ± 8.57 | −18.22 ± 5.6 | −22.97 ± 5.68 | −20.52 ± 4.66 |
AET (ms) | 54.89 ± 6.10 | 45.32 ± 5.99 *,€ | 55.66 ± 8.26 | 56.31 ± 11.07 | 50.68 ± 9.36 | 50.48 ± 5.49 |
IVCT (ms) | 17.38 ± 4.09 | 22.29 ± 4.10 ¥¥ | 18.11 ± 6.36 | 17.64 ± 5.9 | 13.88 ± 4.85 | 13.61 ± 5.33 |
IVRT (ms) | 16.25 ± 2.44 | 26.22 ± 5.59 **** | 19.80 ± 3.49 | 21.83 ± 4.24 | 15.38 ± 4.23 | 21.25 ± 2.93 *,¥ |
MV A velocity (mm/s) | 441.59 ± 64.77 | 403.32 ± 88.07 | 369.08 ± 104.75 †† | 427.26 ± 145.15 | 537.07 ± 153.3 | 467.34 ± 109.2 |
MV E velocity(mm/s) | 655.76 ± 90.86 | 490.88 ± 162.26 * | 796.53 ± 83.88 | 686.76 ± 186.83 €€ | 763.44 ± 115.15 | 762 ± 59 ± 136.31 ¥¥¥¥ |
E/A ratio | 1.51 ± 0.30 | 1.24 ± 0.36 | 2.3 ± 1.66 €€,† | 1.66 ± 0.33 | 1.49 ± 0.31 | 1.75 + 0.47 |
DT (ms) | 23.66 ± 3.68 | 21.14 ± 4.69 | 26.97 ± 7.6 | 26.22 ± 6.23 | 22.07 ± 5.11 | 29.67 ± 5.84 *,¥ |
MV E/E′ ratio | 31.74 ± 5.53 | 32.77 ± 11.28 | 41.06 ± 15.73 | 40.89 ± 18.01 | 34.71 ± 8.53 | 38.58 ± 9.79 |
Mean Velocity (MV VTI, mm/s) | 357.44 ± 58.47 | 302.7 ± 77.60 | 414.46 ± 55.58 | 351.97 ± 68.80 | 428.65 ± 81.06 | 384.62 ± 75.82 |
Mean Gradient (MV VTI, mmHg) | 0.52 ± 0.16 | 0.39 ± 0.21 | 0.70 ± 0.19 | 0.51 ± 0.20 | 0.76 ± 0.28 | 0.61 ± 0.24 |
Peak Velocity (MV VTI, mm/s) | 670.60 ± 83.69 | 522.73 ± 151.4 ¥ | 807.11 ± 76.82 | 693.46 ± 187.52 | 768.38 ± 116.04 | 767.23 ± 133.64 |
Peak Gradient (MV VTI, mmHg) | 1.83 ± 0.45 | 1.18 ± 0.71 ¥ | 2.64 ± 0.52 | 2.05 ± 1.06 | 2.42 ± 0.72 | 2.42 ± 0.86 |
NFT (ms) | 89.47 ± 9.24 | 93.37 ± 13.65 | 94.22 ± 14.46 | 96.03 ± 13.92 | 82.04 ± 13.59 | 86.31 ± 12.36 |
A′/E′ | 1.06 ± 0.14 | 1.16 ± 0.2 ¥¥¥ | 0.92 ± 0.23 | 0.96 ± 0.30 | 1.00 ± 0.3 | 0.74 ± 0.12 |
E′/A′ | 0.96 ± 0.13 | 0.87 ± 0.18 ¥¥¥ | 1.15 ± 0.30 | 1.15 ± 0.38 | 1.08 ± 0.3 | 1.38 ± 0.22 |
LV MPI (Tei Index) | 0.63 ± 0.12 | 1.06 ± 0.16 *** | 0.73 ± 0.16 | 0.73 ± 0.19 €€ | 0.63 ± 0.15 | 0.71 ± 0.16 ¥¥ |
Cardiac dimensions | ||||||
WT (n = 14) | Col4a3-/-(n = 15) | WT (n = 14) | Col4a3-/- (n = 10) | WT (n = 11) | Col4a3-/- (n = 10) | |
Area, d (mm2) | 21.19 ± 1.72 | 18.97 ± 2.60 | 20.53 ± 2.71 | 19.75 ± 2.63 | 20.43 ± 2.78 | 21.77 ± 2.25 |
Area, s (mm2) | 14.02 ± 1.39 | 13.59 ± 3.24 | 14.54 ± 2.20 | 14.18 ±2.48 | 12.45 ± 2.59 | 15.18 ± 6.61 |
Endo major, d (mm) | 7.19 ± 0.36 | 6.95 ± 0.29 | 7.27 ± 0.53 | 6.91 ± 0.48 | 7.21± 0.40 | 7.22 ± 0.38 |
Endo major, s (mm) | 6.33 ± 0.32 | 6.19 ± 0.63 | 6.64 ± 0.52 | 6.28 ± 0.50 | 6.24 ± 0.49 | 6.62 ± 0.43 |
Epi major, d (mm) | 7.34 ±0.35 | 7.70 ± 0.46 | 7.81 ± 0.55 | 7.43 ± 0.48 | 7.84 ± 0.32 | 7.89 ± 0.37 |
Epi major, s (mm) | 6.90 ± 0.35 | 6.84 ± 0.59 | 7.16 ± 0.54 | 6.88 ± 0.46 | 6.99 ± 0.38 | 7.32 ± 0.42 |
LV mass (mg) | 106.80±17.0 | 104.96±15.45 | 89.44 ± 12.25 ††† | 99.41 ± 17.17 † | 118.38±19.38 | 123.62±14.13 |
LV mass/BW (mg/g) | 4.82 ± 0.64 | 5.68 ± 0.79 * | 4.1 ± 0.47 | 5.01 ± 1.01 | 4.11 ± 0.61 | 4.57 ± 0.66 ¥¥ |
LVAW, d (mm) | 0.77 ± 0.08 | 0.86 ± 0.18 | 0.66 ± 0.13 | 0.83 ± 0.19 | 0.82 ± 0.13 | 0.74 ± 0.12 |
LVAW, s (mm) | 1.03 ± 0.15 | 1.16 ± 0.28 | 0.94 ± 0.21† | 1.08 ± 0.29 | 1.21 ± 0.23 | 1.05 ± 0.19 |
LVPW, d (mm) | 0.78 ± 0.17 | 0.79 ± 0.14 € | 0.66 ± 0.09 | 0.64 ± 0.101 | 0.72 ± 0.08 | 0.72 ± 0.06 |
LVPW, s (mm) | 0.97 ± 0.16 | 0.98 ± 0.15 | 0.85 ±0.08†† | 0.84 ± 0.09 | 1.08 ±0.18 | 0.97 ± 0.12 |
LVID, d (mm) | 3.84 ± 0.23 | 3.56 ± 0.35 ¥¥¥ | 3.88 ± 0.34 | 3.81 ± 0.19 † | 4.0 ± 0.39 | 4.2 ± 0.17 |
LVID, s (mm) | 2.88 ± 0.43 | 2.68 ± 0.53 ¥ | 2.95 ± 0.26 | 2.94 ± 0.37 | 2.82 ± 0.62 | 3.21 ±0.29 |
Echocardiography Parameters | 129J 8 Weeks Old | Balb/C 8 Weeks Old | C57Bl/6 20 Weeks Old | |||
---|---|---|---|---|---|---|
Systolic function | ||||||
WT (n = 13) | Col4a3-/- (n = 16) | WT (n = 13) | Col4a3-/- (n = 15) | WT (n = 14) | Col4a3-/- (n = 11) | |
EF (%) | 64.75 ± 9.3 | 52.17 ± 10.73 ** | 53.1± 8.35 € | 44.09 ± 10.97 | 58.48 ± 8.31 | 42.21 ± 8.49 *** |
SV (µL) | 34.49 ± 6.32 | 29.15 ± 6.53 | 30.94 ± 5.6 | 22.93 ± 6.46 * | 32.46 ± 4.27 | 31.02 ± 7.72 † |
CO (µL/min) | 15.38 ± 3.17 | 12.1 ± 3.65 * | 12.37 ± 2.085 | 9.06 ± 2.68 | 15.34 ± 2.42 | 14.03 ± 3.3 †† |
FS (%) | 35.07 ± 6.65 | 26.56 ± 7.01 * | 27.07 ± 5.28 | 21.55 ± 6.22 | 30.63 ± 6.17 | 20.64 ± 4.9 ** |
ESV (µL) | 18.87 ± 5.59 € | 27.42 ± 9.4 *,¥¥¥¥ | 27.72 ± 7.44 | 29.07 ± 7.22 ††† | 23.85 ± 7.12 | 42.53 ± 8.82 **** |
EDV (µL) | 53.35 ± 6.9 | 56.57 ± 10.58 | 58.66 ± 8.88 | 52 ± 8.68 †† | 57.7 ± 8.12 | 71.86 ± 11.23 |
HR (bpm) | 448.88 ± 43.06 | 418.16 ± 38.21 | 429.53 ± 23.30 † | 412.80 ± 48.60 | 477.75 ± 40.40 | 450.77 ± 39.50 |
GLS (%) | −19.39 ± 2.45 | −13.73 ± 3.16 ** | −15.38 ± 3.16 | −13.72 ± 4.48 | −18.51 ± 2.78 | −15.39 ± 6.68 |
GCS (%) | −23.34 ± 5.68 | −15.27 ± 5.26 ** | −15.3 ± 2.87 €€,† | −13.84 ± 3.82 | −21.32 ± 3.28 | −14.06 ± 4.42 ** |
Diastolic function | ||||||
WT (n = 13) | Col4a3-/-(n = 16) | WT (n = 13) | Col4a3-/- (n = 15) | WT (n = 14) | Col4a3-/-(n = 11) | |
A′ velocity (mms/s) | −21.48 ± 3.54 | −21.23 ± 6.21 | −17.17 ± 5.12 | −19.05 ± 4.58 | −20.67 ± 7.13 | −18.27 ± 4.32 |
E′ velocity (mm/s) | −23.25 ± 4.67 | −19.76 ± 6.74 | −20.22 ± 6.50 | −18.11 ± 7.14 | −24.87 ± 4.40 | −21.62 ± 4.76 |
AET (ms) | 48.78 ± 5.80 | 49.50 ± 5.57 | 60.83 ± 8.08 €€€€ | 56.42 ± 7.15 € | 50.42 ± 4.26 ††† | 47.73 ± 6.8 † |
IVCT (ms) | 17.18 ± 4.0 | 19.82 ± 3.80 | 15.36 ± 6.43 | 22.12 ± 7.94 * | 15.73 ± 5.05 | 22.40 ± 7.25 |
IVRT (ms) | 15.32 ± 2.83 | 22.27 ± 5.35 ** | 16.01 ± 2.88 | 24.92 ± 5.10 **** | 17.44 ± 4.10 | 22.73 ± 5.40 * |
MV A velocity (mm/s) | 463.80 ± 80.98 | 434.08 ± 110.99 | 330.59 ± 68.99 † | 353.43 ± 130.98 | 474.39 ±159.92 | 359.06 ± 163.32 |
MV E velocity(mm/s) | 739.94 ± 141.21 | 589.35 ± 117.47 ¥¥ | 774.37 ± 141.74 | 685.81 ± 145.70 | 816.64 ± 189.27 | 783.16 ± 160.59 |
E/A ratio | 1.53 ± 0.30 €€ | 1.42 ± 0.36 €,¥¥ | 2.43 ± 0.60 | 2.13 ± 0.72 | 1.79 ± 0.74 | 2.41 ± 0.84 |
DT (ms) | 18.59 ± 2.94 €€€ | 20.16 ± 3.58 | 27.23 ± 4.48 | 25.43 ± 7.49 | 19.44 ± 5.11 †† | 18.32 ± 4.99 †† |
MV E/E′ ratio | 32.63 ± 7.04 | 32.73 ± 10.50 | 39.83 ± 14.56 | 40.47 ± 15.85 | 33.13 ± 6.52 | 37.71 ± 11.1 |
Mean Velocity (MV VTI, mm/s) | 428.37 ± 79.15 | 348.63 ± 68.52 | 376.39 ± 89.42 | 365.36 ± 82.51 | 444.68 ± 78.08 | 404.03 ± 95.04 |
Mean Gradient (MV VTI, mmHg) | 0.76 ± 0.3 | 0.50 ± 0.20 | 0.63 ± 0.27 | 0.56 ± 0.27 | 0.81 ± 0.32 | 0.69 ± 0.32 |
Peak Velocity (MV VTI, mm/s) | 748.39 ± 140.78 | 605.08 ± 112.36 ¥ | 777.75 ± 146.00 | 682.06 ± 145.09 | 815.08 ± 188 | 775.7 ± 173.64 |
Peak Gradient (MV VTI, mmHg) | 2.32 ± 0.89 | 1.51 ± 0.59 ¥ | 2.51 ± 1.94 | 1.94 ± 0.86 | 2.79 ± 1.39 | 2.52 ± 1.02 |
NFT (ms) | 82.05 ± 6.42 | 90.88 ± 11.23 | 91.97 ± 9.01 | 103.86 ± 14.90 | 85.62 ± 9.02 | 94.28 ± 11.3 |
A′/E′ | 0.95 ± 0.23 | 1.14 ± 0.29 | 0.88 ± 0.2 | 1.17± 0.39 | 0.84 ± 0.29 | 0.85 ± 0.132 |
E′/A′ | 1.10 ± 0.25 | 0.94 ± 0.28 | 1.19 ± 0.27 | 0.95 ± 0.33 | 1.33 ± 0.47 | 1.20 ± 0.21 |
LV MPI (Tei Index) | 0.69 ± 0.14 | 0.83 ± 0.15 | 0.53 ± 0.21 | 0.81 ± 0.18 * | 0.70 ± 0.16 | 1.0 ± 0.36 ** |
Cardiac dimensions | ||||||
WT (n = 13) | Col4a3-/- (n = 16) | WT (n = 13) | Col4a3-/- (n = 15) | WT (n = 14) | Col4a3-/- (n = 11) | |
Area, d (mm2) | 17.31 ± 1.39 | 18.16 ± 1.35 | 18.02 ± 1.37 | 18.04 ± 2.27 | 19.68 ± 3.6 | 21.80 ± 1.50 ¥¥¥,†† |
Area, s (mm2) | 10.36 ± 1.34 | 13.04 ± 10.65 * | 11.90 ± 1.60 | 12.71 ± 2.44 | 12.14 ± 3.09 | 15.88 ± 2.0 ***,¥,††† |
Endo major, d (mm) | 6.41 ± 0.42 ¥¥ | 6.53 ± 0.33 ¥¥ | 6.83 ± 0.33 | 6.88 ± 0.44 | 7.02 ± 0.75 | 7.33 ± 0.37 |
Endo major, s (mm) | 5.43 ± 0.22 €€,¥¥ | 5.72 ± 0.43 €,¥¥ | 6.16 ± 0.38 | 6.33 ± 0.40 | 6.13 ± 0.73 | 6.67 ± 0.44 |
Epi major, d (mm) | 6.89 ± 0.38 ¥¥ | 7.13 ± 0.33 ¥¥ | 7.35 ± 0.31 | 7.39 ± 0.46 | 7.57 ± 0.82 | 7.89 ± 0.31 |
Epi major, s (mm) | 5.96 ± 0.25 ¥¥¥,€ | 6.40 ± 0.44 ¥¥¥ | 6.71 ± 0.37 | 6.88 ± 0.44 | 6.94 ± 0.50 | 7.27 ± 0.32 |
LV mass (mg) | 79.35 ± 12.15 | 83.70 ± 13.55 ¥ | 86.64 ± 16.41 | 74.33 ± 20.60 † | 84.81 ± 14.19 | 107.03 ± 15.5 |
LV mass/BW (mg/g) | 4.5 ± 0.45 | 5.11 ± 0.87 | 4.88 ± 0.83 | 4.33 ± 1.03 | 4.21 ± 0.61 | 4.90 ± 0.65 |
LVAW, d (mm) | 0.73 ± 0.088 | 0.72 ± 0.054 | 0.69 ± 0.132 | 0.66 ± 0.113 | 0.69 ± 0.13 | 0.66 ± 0.11 |
LVAW, s (mm) | 0.95 ± 0.15 | 0.94 ± 0.12 | 0.95 ± 0.14 | 0.88 ± 0.13 | 1.10 ± 0.12 | 0.96 ± 0.22 |
LVPW, d (mm) | 0.66 ± 0.09 | 0.71 ± 0.12 | 0.67 ± 0.10 | 0.66 ± 0.15 | 0.73 ± 0.12 | 0.74 ±0.11 |
LVPW, s (mm) | 0.94 ± 0.11 | 0.89 ± 0.11 | 0.90 ± 0.12 | 0.81 ± 0.21 | 1.04 ± 0.15 | 0.96 ± 0.17 |
LVID, d (mm) | 3.42 ± 0.19 | 3.51 ± 0.31 ¥¥¥¥ | 3.65 ± 0.27 | 3.48 ± 0.25 †††† | 3.63 ± 0.27 | 4.03 ± 0.27 ** |
LVID, s (mm) | 2.42 ± 0.27 | 2.78 ± 0.38 ¥ | 2.78 ± 0.28 | 2.77 ± 0.32 † | 2.57 ± 0.38 | 3.2 ± 0.31 *** |
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Irion, C.I.; Williams, M.; Capcha, J.C.; Eisenberg, T.; Lambert, G.; Takeuchi, L.M.; Seo, G.; Yousefi, K.; Kanashiro-Takeuchi, R.; Webster, K.A.; et al. Col4a3-/- Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over-Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds. Int. J. Mol. Sci. 2022, 23, 6674. https://doi.org/10.3390/ijms23126674
Irion CI, Williams M, Capcha JC, Eisenberg T, Lambert G, Takeuchi LM, Seo G, Yousefi K, Kanashiro-Takeuchi R, Webster KA, et al. Col4a3-/- Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over-Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds. International Journal of Molecular Sciences. 2022; 23(12):6674. https://doi.org/10.3390/ijms23126674
Chicago/Turabian StyleIrion, Camila I., Monique Williams, Jose Condor Capcha, Trevor Eisenberg, Guerline Lambert, Lauro M. Takeuchi, Grace Seo, Keyvan Yousefi, Rosemeire Kanashiro-Takeuchi, Keith A. Webster, and et al. 2022. "Col4a3-/- Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over-Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds" International Journal of Molecular Sciences 23, no. 12: 6674. https://doi.org/10.3390/ijms23126674