Lipidomics Reveals Cisplatin-Induced Renal Lipid Alterations during Acute Kidney Injury and Their Attenuation by Cilastatin
Abstract
:1. Introduction
2. Results
2.1. Cilastatin Protective Effect against Cisplatin-Induced Renal Damage
2.2. Cisplatin Alteration of Global Renal Lipids Classes in the Cortex and Medulla. Protective Effect of Cilastatin
2.3. Individual Renal Lipid Species Alteration by Cisplatin Treatment. Cilastatin Attenuating Effect
2.3.1. Cholesterol Esters
2.3.2. Sphingolipids: Cer, dhCer, HexCer, dhHexCer, SM, dhSM, and Sulf
2.3.3. Phospholipids: PC, PE, and LPC
2.4. Renal Lipids as Classification Variables for Kidney Damage and Protection
2.5. Renal Lipids as Potential Biomarkers of Cisplatin-Induced Renal Damage
2.6. Renal Lipids as Potential Biomarkers of Cilastatin Nephroprotection
3. Discussion
4. Materials and Methods
4.1. Reagents
4.2. Animal Model
4.3. Histological Studies
4.4. Renal Function Indicators
4.5. Tissue Homogenization
4.6. Lipidomic Analysis by LC-MS/MS
4.7. Statistical Analysis
5. Patents
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Group | S Cr (mg/dL) | BUN (mg/dL) | GFR (mL/min/100 g) | Prot urine (mg/dL) | FE Na+ (%) | FE K+ (%) | Vol Urine 24 h (mL) |
---|---|---|---|---|---|---|---|
Control | 0.31 ± 0.06 | 33 ± 7 | 2.3 ± 0.5 | 30 ± 6 | 0.5 ± 0.1 | 20 ± 5 | 14 ± 2 |
Cilastatin | 0.33 ± 0.05 | 30 ± 6 | 2.0 ± 0.5 | 28 ± 7 | 0.53 ± 0.09 | 21 ± 3 | 14 ± 6 |
Cisplatin | 1.4 ± 0.8 a | 110 ± 70 a | 0.4 ± 0.2 a | 40 ± 8 a | 2 ± 1 a | 70 ± 40 a | 26 ± 4 a |
Cisplatin + cilastatin | 0.6 ± 0.2 | 50 ± 10 | 1.0 ± 0.3 b | 30 ± 5 | 0.8 ± 0.2 | 31 ± 9 | 20 ± 10 |
Lipid (Cortex) | FC | Trend | p-Value | p(corr) | VIP Score | AUC ROC |
---|---|---|---|---|---|---|
CE 18:0 | 20.16 | ↑ | 0.00079 | 0.974 | 3.18 | 1 |
CE 18:1 | 6.62 | ↑ | 0.00020 | 0.983 | 2.53 | 1 |
CE 18:2 | 5.86 | ↑ | 2.28 × 10−6 | 0.964 | 2.44 | 1 |
CE 20:4 | 8.12 | ↑ | 0.00216 | 0.985 | 2.64 | 1 |
CE 22:6 | 18.35 | ↑ | 0.00088 | 0.985 | 3.10 | 1 |
Cer 40:1 | 1.70 | ↑ | 0.00074 | 0.823 | 1.22 | 0.944 |
dhCer 36:0 | 1.59 | ↑ | 0.01193 | 0.748 | 1.12 | 0.917 |
dhHexCer 34:0 | 2.00 | ↑ | 0.00384 | 0.721 | 1.39 | 0.972 |
dhHexCer 36:0 | 1.79 | ↑ | 0.01704 | 0.651 | 1.27 | 0.861 |
dhHexCer 38:0 | 1.85 | ↑ | 0.01409 | 0.620 | 1.28 | 0.861 |
dhSM 34:0 | 0.61 | ↓ | 0.00866 | −0.866 | 1.23 | 0.944 |
dhSM 36:0 | 1.77 | ↑ | 0.00158 | 0.817 | 1.24 | 1 |
HexCer 34:1 | 1.50 | ↑ | 0.00491 | 0.737 | 1.06 | 0.944 |
LPC 16:1 | 0.70 | ↓ | 0.00216 | −0.903 | 1.09 | 1 |
LPC 18:0 | 0.67 | ↓ | 0.00001 | −0.909 | 1.14 | 1 |
LPC 20:3 | 0.69 | ↓ | 0.00018 | −0.900 | 1.08 | 1 |
PC 34:5 | 0.57 | ↓ | 0.00010 | −0.873 | 1.33 | 1 |
PC 36:5 | 0.55 | ↓ | 0.00016 | −0.902 | 1.37 | 1 |
PC 36:6 | 0.58 | ↓ | 0.00001 | −0.955 | 1.32 | 1 |
PC 40:6 | 0.62 | ↓ | 0.00433 | −0.840 | 1.18 | 0.972 |
PE 36:5 | 0.54 | ↓ | 6.33 × 10−7 | −0.965 | 1.44 | 1 |
PE 38:3 | 0.66 | ↓ | 0.00782 | −0.662 | 1.07 | 0.944 |
SM 34:1 | 0.71 | ↓ | 0.00050 | −0.868 | 1.02 | 1 |
Sulf 42:0 | 0.43 | ↓ | 0.00799 | −0.870 | 1.56 | 1 |
Sulf OH-40:1 | 0.36 | ↓ | 0.00196 | −0.912 | 1.80 | 1 |
Sulf OH-42:1 | 0.43 | ↓ | 0.00219 | −0.903 | 1.59 | 1 |
Sulf OH-42:2 | 0.51 | ↓ | 0.00896 | −0.799 | 1.37 | 0.944 |
Lipid (Medulla) | FC | Trend | p-Value | p(corr) | VIP Score | AUC ROC |
---|---|---|---|---|---|---|
CE 18:0 | 18.44 | ↑ | 1.98 × 10−9 | 0.969 | 2.60 | 1 |
CE 18:1 | 5.77 | ↑ | 0.0002 | 0.977 | 2.01 | 1 |
CE 18:2 | 2.95 | ↑ | 0.0001 | 0.989 | 1.60 | 1 |
CE 20:4 | 2.88 | ↑ | 0.0005 | 0.942 | 1.54 | 1 |
CE 22:6 | 5.05 | ↑ | 0.0002 | 0.914 | 1.82 | 1 |
Cer 36:1 | 1.74 | ↑ | 0.0019 | 0.804 | 1.13 | 0.917 |
Cer 38:1 | 2.02 | ↑ | 0.0003 | 0.861 | 1.26 | 0.972 |
Cer 40:1 | 2.52 | ↑ | 0.0022 | 0.928 | 1.47 | 1 |
Cer 42:1 | 2.26 | ↑ | 8.63 × 10−6 | 0.965 | 1.36 | 1 |
Cer 42:2 | 2.77 | ↑ | 0.0022 | 0.951 | 1.52 | 1 |
dhCer 34:0 | 1.83 | ↑ | 7.71 × 10−6 | 0.948 | 1.19 | 1 |
dhCer 36:0 | 2.19 | ↑ | 0.0001 | 0.916 | 1.35 | 1 |
dhCer 38:0 | 2.06 | ↑ | 0.0006 | 0.840 | 1.27 | 0.944 |
dhCer 40:0 | 1.71 | ↑ | 0.0152 | 0.797 | 1.09 | 0.917 |
dhCer 42:1 | 1.86 | ↑ | 0.0003 | 0.894 | 1.17 | 1 |
dhHexCer 36:0 | 2.27 | ↑ | 0.0022 | 0.877 | 1.35 | 1 |
dhHexCer 38:0 | 1.77 | ↑ | 0.0130 | 0.650 | 1.16 | 0.917 |
dhSM 36:0 | 1.84 | ↑ | 1.23 × 10−5 | 0.933 | 1.18 | 1 |
dhSM 40:0 | 1.56 | ↑ | 0.0071 | 0.743 | 1.00 | 0.944 |
HexCer 34:1 | 2.46 | ↑ | 1.25 × 10−6 | 0.903 | 1.42 | 1 |
HexCer 36:1 | 2.47 | ↑ | 2.59 × 10−6 | 0.907 | 1.41 | 1 |
HexCer 38:1 | 1.86 | ↑ | 0.0024 | 0.741 | 1.19 | 0.972 |
PC 34:5 | 0.39 | ↓ | 2.83 × 10−6 | −0.933 | 1.46 | 1 |
PC 36:5 | 0.37 | ↓ | 0.0022 | −0.961 | 1.55 | 1 |
PC 36:6 | 0.37 | ↓ | 0.0001 | −0.954 | 1.55 | 1 |
PC 38:7 | 0.49 | ↓ | 0.0001 | −0.933 | 1.28 | 1 |
PC 40:7 | 0.51 | ↓ | 0.0022 | −0.953 | 1.26 | 1 |
PE 34:1 | 0.61 | ↓ | 0.0022 | −0.881 | 1.08 | 1 |
PE 34:2 | 0.59 | ↓ | 0.0001 | −0.933 | 1.10 | 1 |
PE 34:3 | 0.49 | ↓ | 1.28 × 10−5 | −0.973 | 1.29 | 1 |
PE 36:4 | 0.51 | ↓ | 0.0022 | −0.951 | 1.27 | 1 |
PE 36:5 | 0.26 | ↓ | 0.0022 | −0.989 | 1.77 | 1 |
PE 38:3 | 0.64 | ↓ | 0.0002 | −0.922 | 1.02 | 1 |
PE 38:4 | 0.61 | ↓ | 0.0005 | −0.889 | 1.05 | 0.972 |
PE 38:5 | 0.48 | ↓ | 0.0022 | −0.969 | 1.31 | 1 |
PE 38:6 | 0.51 | ↓ | 0.0022 | −0.920 | 1.26 | 1 |
PE 38:7 | 0.45 | ↓ | 0.0001 | −0.955 | 1.37 | 1 |
PE 40:4 | 1.83 | ↑ | 0.0043 | 0.841 | 1.16 | 0.972 |
SM 34:1 | 0.61 | ↓ | 0.0022 | −0.872 | 1.07 | 1 |
Sulf 40:2 | 0.40 | ↓ | 0.0022 | −0.777 | 1.48 | 1 |
Lipid (Cortex) | FC CISCIL vs. CISPL | FC CISPL vs. CNT | FC CISCIL vs. CNT | p Value CISCIL vs. CISPL | p(corr) | VIP Score | AUC ROC |
---|---|---|---|---|---|---|---|
CE 18:0 | 0.40 a | 20.16 a | 8.08 a | 0.0051 | −0.912 | 2.49 | 1 |
CE 18:1 | 0.44 a | 6.62 a | 2.94 a | 0.0004 | −0.912 | 2.41 | 1 |
CE 18:2 | 0.38 a | 5.86 a | 2.24 a | 0.0004 | −0.896 | 2.57 | 1 |
CE 20:4 | 0.40 a | 8.12 a | 3.25 a | 0.0007 | −0.931 | 2.53 | 1 |
CE 22:6 | 0.32 a | 18.35 a | 5.83 a | 0.0031 | −0.935 | 2.80 | 1 |
Cer 40:1 | 0.71 a | 1.70 a | 1.20 a | 0.0060 | −0.714 | 1.44 | 0.889 |
dhHexCer 34:0 | 0.57 a | 2.00 a | 1.14 | 0.0117 | −0.709 | 1.88 | 0.917 |
PC 32:2 | 0.80 a | 1.12 | 0.89 | 0.0053 | −0.787 | 1.21 | 0.944 |
PE 36:5 | 1.21 a | 0.54 a | 0.65 a | 0.0118 | 0.746 | 1.08 | 0.889 |
Sulf 38:1 | 0.78 a | 1.16 | 0.90 | 0.0101 | −0.758 | 1.31 | 0.861 |
Sulf 40:2 | 0.40 a | 1.00 | 0.41 a | 0.0028 | −0.797 | 2.17 | 1 |
Lipid (Medulla) | FC CISCIL vs. CISPL | FC CISPL vs. CNT | FC CISCIL vs. CNT | p-Value CISCIL vs. CISPL | p(corr) | VIP Score | AUC ROC |
---|---|---|---|---|---|---|---|
CE 18:2 | 0.64 a | 2.95 a | 1.89 a | 0.0039 | −0.864 | 1.53 | 0.917 |
Cer 42:2 | 0.69 a | 2.77 a | 1.92 a | 0.0087 | −0.720 | 1.36 | 0.944 |
dhHexCer 36:0 | 0.62 a | 2.27 a | 1.40 | 0.0022 | −0.637 | 1.45 | 1 |
HexCer 34:1 | 0.72 a | 2.46 a | 1.78 a | 0.0123 | −0.659 | 1.26 | 0.972 |
PC 32:1 | 1.32 a | 0.63 a | 0.84 | 0.0047 | 0.741 | 1.04 | 0.944 |
PC 36:5 | 1.58 a | 0.37 a | 0.58 a | 0.0087 | 0.817 | 1.44 | 0.944 |
PC 36:6 | 1.71 a | 0.37 a | 0.63 a | 0.0030 | 0.875 | 1.63 | 0.944 |
PE 34:2 | 1.51 a | 0.59 a | 0.89 | 0.0082 | 0.689 | 1.24 | 0.944 |
PE 34:3 | 1.63 a | 0.49 a | 0.80 | 0.0022 | 0.935 | 1.54 | 1 |
PE 36:3 | 1.29 a | 0.76 a | 0.98 | 0.0040 | 0.794 | 1.04 | 0.944 |
PE 36:4 | 1.57 a | 0.51 a | 0.80 | 0.0087 | 0.654 | 1.29 | 0.944 |
PE 36:5 | 1.94 a | 0.26 a | 0.51 a | 0.0022 | 0.960 | 1.78 | 1 |
PE 38:5 | 1.55 a | 0.48 a | 0.74 a | 0.0022 | 0.854 | 1.39 | 1 |
PE 38:6 | 1.54 a | 0.51 a | 0.79 | 0.0130 | 0.811 | 1.44 | 0.917 |
SM 42:1 | 1.49 a | 0.71 a | 1.07 | 0.0115 | 0.756 | 1.33 | 0.889 |
Sulf 40:2 | 2.47 a | 0.40 a | 0.98 | 0.0049 | 0.720 | 2.01 | 0.917 |
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Moreno-Gordaliza, E.; Marazuela, M.D.; Pastor, Ó.; Lázaro, A.; Gómez-Gómez, M.M. Lipidomics Reveals Cisplatin-Induced Renal Lipid Alterations during Acute Kidney Injury and Their Attenuation by Cilastatin. Int. J. Mol. Sci. 2021, 22, 12521. https://doi.org/10.3390/ijms222212521
Moreno-Gordaliza E, Marazuela MD, Pastor Ó, Lázaro A, Gómez-Gómez MM. Lipidomics Reveals Cisplatin-Induced Renal Lipid Alterations during Acute Kidney Injury and Their Attenuation by Cilastatin. International Journal of Molecular Sciences. 2021; 22(22):12521. https://doi.org/10.3390/ijms222212521
Chicago/Turabian StyleMoreno-Gordaliza, Estefanía, Maria Dolores Marazuela, Óscar Pastor, Alberto Lázaro, and María Milagros Gómez-Gómez. 2021. "Lipidomics Reveals Cisplatin-Induced Renal Lipid Alterations during Acute Kidney Injury and Their Attenuation by Cilastatin" International Journal of Molecular Sciences 22, no. 22: 12521. https://doi.org/10.3390/ijms222212521