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Anti-Inflammatory Therapy Modulates Nrf2-Keap1 in Kidney from Rats with Diabetes
Abraham Said Arellano-Buendía1, Montserrat Tostado-González1, Fernando Enrique García-Arroyo1
1Laboratory of Renal Physiopathology, Juan Badiano 1, 14080 Mexico City, DF, Mexico; Department of Nephrology, Instituto Nacional de Cardiología-Ignacio Chávez, Juan Badiano 1, 14080 Mexico City, DF, Mexico.
Abstract:
This study addressed the relationship of proinflammatory cytokines and Nrf2-Keap1 system in diabetic nephropathy. The experimental groups were control, diabetic, and diabetic treated with mycophenolate mofetil (MMF). The renal function, proinflammatory and profibrotic cytokines, oxidative stress, morphology, and nephrin expression were assessed. Diabetic group showed impaired renal function in association with oxidative stress and decreased Nrf2 nuclear translocation. These results were associated with increased mesangial matrix index, interstitial fibrosis, and increased nephrin expression in cortex and urine excretion. Additionally, interleukin-1β, IL-6, and transforming growth factor-β1 were increased in plasma and kidney. MMF treatment conserved renal function, prevented renal structural alterations, and partially prevented the proinflammatory and profibrotic cytokines overexpression. Despite that MMF treatment induced nephrin overexpression in renal tissue, preventing its urinary loss. MMF salutary effects were associated with a partial prevention of oxidative stress, increased Nrf2 nuclear translocation, and conservation of antioxidant enzymes in renal tissue. In conclusion, our results confirm that inflammation is a key factor in the progression of diabetic nephropathy and suggest that treatment with MMF protects the kidney by an antioxidant mechanism, possibly regulated at least in part by the Nrf2/Keap1 system, in addition to its well-known anti-inflammatory effects.
Insights
Mycophenolate mofetil (MMF) treatment preserves kidney function in diabetic nephropathy by reducing inflammation and oxidative stress. MMF enhances the Nrf2-Keap1 system, offering protective effects against kidney damage.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Diabetic nephropathy (DN) is a major complication of diabetes, characterized by inflammation and oxidative stress.
- The Nrf2-Keap1 system plays a crucial role in cellular defense against oxidative damage.
Purpose of the Study:
- To investigate the relationship between proinflammatory cytokines, the Nrf2-Keap1 system, and kidney damage in diabetic nephropathy.
- To evaluate the protective effects of mycophenolate mofetil (MMF) in a model of diabetic nephropathy.
Main Methods:
- Experimental groups included control, diabetic, and MMF-treated diabetic rats.
- Assessment of renal function, oxidative stress markers, proinflammatory/profibrotic cytokines (IL-1β, IL-6, TGF-β1), kidney morphology, and nephrin expression.
- Evaluation of Nrf2 nuclear translocation and antioxidant enzyme activity.
Main Results:
- Diabetic rats exhibited impaired renal function, increased oxidative stress, decreased Nrf2 nuclear translocation, and elevated proinflammatory cytokines.
- These changes correlated with mesangial expansion, interstitial fibrosis, and altered nephrin expression.
- MMF treatment improved renal function, attenuated structural damage, reduced cytokine levels, and prevented urinary nephrin loss.
- MMF partially mitigated oxidative stress, increased Nrf2 nuclear translocation, and preserved antioxidant enzyme activity.
Conclusions:
- Inflammation is a critical driver of diabetic nephropathy progression.
- MMF demonstrates protective effects in diabetic nephropathy, acting through both anti-inflammatory and antioxidant mechanisms.
- The Nrf2/Keap1 pathway is implicated in MMF's renoprotective effects in diabetic nephropathy.
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