Metabolic Changes and Oxidative Stress in Diabetic Kidney Disease
Abstract
:1. Introduction
2. Energy Metabolism and Mitochondrial Function in the Kidneys
3. ROS Production and Mitochondrial Dysfunction
4. ER Stress and ROS Production
5. Oxidative Stress in DKD
6. Oxidative Stress and Hypoxia
7. Organelle Crosstalk and Interplay of the Organelle Stress
8. NRF2 as a Master Regulator of Antioxidative Stress
9. NRF2 Function in the Kidneys
10. Oxidative Stress as a Therapeutic Target
11. Results of Previous Clinical Trials or Bardoxolone Methyl for CKD
12. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Disease Model | Intervension | Results of the Study | Ref. |
---|---|---|---|
Aging | Nrf2-KO | Increased mortality and worsened renal function were observed in female mice, with lupus nephritis-like findings accompanied by increased spleen weight and increased ds DNA. | [55,73] |
Lupus nephritis | Nrf2-KO | Nrf2-KO mice showed improved renal function and increased survival rate and reduced immune complex deposition in renal tissue | [74] |
Nrf2-KO | Nrf2-KO mice showed decreased survival, increased spleen weight, increased oxidative stress, and aggravated fibrosis of renal tissue. | [67] | |
DKD (STZ) | Nrf2-KO | Nrf2-KO mice showed a similar increase in blood glucose after STZ administration, but decreased creatinine clearance and urinary albumin excretion, worsened renal pathology, and increased AGE, oxidative stress, and fibrosis markers, which were ameliorated by NRF2 activator administration. | [64,71,75] |
Bilateral IRI | Nrf2-KO | Nrf2-KO mice showed elevated creatinine, worsened histology, and marked elevation of cytokines, but prior administration of N-acetylcysteine suppressed the creatinine elevation. | [65] |
CDDO-Imidazole/Bardoxolone methyl | In the CDDO-Im preadministration group, life expectancy, renal function, and renal tissue damage were improved and acute phase inflammatory cytokines were reduced. | [76,77] | |
Unilateral IRI | Nrf2-KO/Keap1-KD/Keap1-CKO | Nrf2-KO mice showed exacerbation of tubular damage and oxidative stress, while Keap1-KD and Keap1-CKO suppressed creatinine elevation and increased antioxidant markers. | [66] |
Sepsis model | LysM-Keap1-KO/ LysM-Nrf2-KO | LysM-Keap1-KO mice showed improved survival and decreased BUN, AST, and inflammatory cytokines, while LysM-Nrf2-KO mice showed worsening of these parameters. | [78] |
Cisplatin nephropathy | Nrf2-KO/ CDDO-Im | Nrf2-KO mice showed increased mortality, elevated creatinine, and worsened renal tissue damage, while CDDO-Im administration improved renal tissue. | [65,79,80] |
NEP25-induced podocyte injury | Keap1-KD | Improved renal tissue, fibrosis markers, and podocyte damage in Keap1-KD mice. | [81] |
Rhabdomyolysis (myoglobin) nephropathy | - | The expression of downstream genes of Nrf2 was increased in rhabdomyolysis model induced by glycerol administration; chlormethiazole alleviated these changes. | [82] |
5/6 nephrectomy | - | In the 5/6 nephrectomy group, there was a decrease in Nrf2 expression and an increase in Keap1 expression. | [83] |
Adriamycin, Angiotensin II-induced proteinuria | Keap1-KD | Keap1-KD mice showed increased albuminuria in adriamycin nephropathy, the angiotensin II model, and in the protein overload model. | [84] |
Cynomolgus monkeys | bardoxolone methyl | Administration of bardoxolone methyl increased creatinine clearance and urinary albumin; no abnormalities in blood tests or renal tissue were noted after 1 year of treatment. The increase in urinary albumin may be due to decreased megalin expression in the tubules. | [85] |
Phase | Kidney Function | Patient Number | Dose (mg/day) | Duration | ΔeGFR (Average ± S.D.) (mL/min/1.73m2) |
---|---|---|---|---|---|
1st [91] | Ccr ≥ 60 or Cr < 2.0 eGFR < 60 (sub analysis) | 36 (10) | 5–1300 5–1300 | 21 days 21 days | 26.4% ± 3.2% 35.6% ± 6.8% |
2nd [95] | man 1.5 ≤ Cr ≤ 3.0, woman 1.3 ≤ Cr ≤ 3.0 | 18 | 25–75 | 8 weeks | 7.2 ± 5.3 |
2nd (BEAM [96]) | 20 ≤ eGFR ≤ 45 | 227 | 25 25–75 25–100 | 24/52 weeks | Results in 24 wk/52 wk 8.2 ± 1.5/ 5.8 ± 1.8 11.4 ± 1.5/ 10.5 ± 1.8 10.4 ± 1.5/ 9.3 ± 1.9 |
3rd (BEACON [97]) | 15 ≤ eGFR < 30 | 2185 | 20 | 9 months | 5.5 ± 0.2 |
2nd (TSUBAKI [99]) | 30 ≤ eGFR < 60 ACR < 300, 15 ≤ eGFR < 30 ACR < 2000 | 120 | 5–15 | 16 weeks | 6.64 |
3rd (AYAME) | 15 ≤ eGFR < 60, ACR ≤ 3500 | (700) | 5–15 | 2–3 years | (ongoing) |
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Sakashita, M.; Tanaka, T.; Inagi, R. Metabolic Changes and Oxidative Stress in Diabetic Kidney Disease. Antioxidants 2021, 10, 1143. https://doi.org/10.3390/antiox10071143
Sakashita M, Tanaka T, Inagi R. Metabolic Changes and Oxidative Stress in Diabetic Kidney Disease. Antioxidants. 2021; 10(7):1143. https://doi.org/10.3390/antiox10071143
Chicago/Turabian StyleSakashita, Midori, Tetsuhiro Tanaka, and Reiko Inagi. 2021. "Metabolic Changes and Oxidative Stress in Diabetic Kidney Disease" Antioxidants 10, no. 7: 1143. https://doi.org/10.3390/antiox10071143
APA StyleSakashita, M., Tanaka, T., & Inagi, R. (2021). Metabolic Changes and Oxidative Stress in Diabetic Kidney Disease. Antioxidants, 10(7), 1143. https://doi.org/10.3390/antiox10071143