Anti‐Inflammatory Therapy Modulates Nrf2‐Keap1 in Kidney from Rats with Diabetes

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.

Extracellular Superoxide Dismutase Attenuates Renal Oxidative Stress Through the Activation of Adenosine Monophosphate-Activated Protein Kinase in Diabetic Nephropathy

“…Among these cytokines and chemokines, MCP-1 and TNF-a are central to the pathogenesis of inflammatory damage in DN (3,46). The Nrf2-Keap1 system also plays an important role in reducing inflammation in DN (2,47). Recent studies demonstrated that EC-SOD modulates innate and adaptive immune responses, ameliorating the progression of skin and airway inflammation (33,36).…”

“…PGC-1a also acts upstream of the nuclear factor E2related factor 2 (Nrf2)-antioxidant response element pathway to increase transcription of Nrf2 (30). Nrf2 regulates cellular detoxification responses and redox status in chronic kidney disease and DN (2,25). EC-SOD is mainly synthesized by vascular smooth muscle cells and fibroblasts (44).…”

The Effect of Nrf2 on Diabetic Complications

“…Several studies report the iniltration of macrophages and proinlammatory cells in kidney at diferent stages of DN [26]. The inlammatory iniltrate produces reactive oxygen species (ROS), proinlammatory cytokines, and growth factors, which lead to upregulation of chronic systemic inlammation and mediate the progression of diabetic nephropathy [26,[28][29][30].…”

“…Thus, chronic inlammation contributes to DN not only as a consequence of a direct efect of proinlammatory mediators on cellular signaling but also by creating a state of oxidative stress. In recent years, several investigators have provided substantial evidence implicating nuclear factor Nrf2 in inlammation and associated disorders [30,31].…”

“…Oxidative stress and inlammation are mediators in the development and progression of chronic kidney disease (CKD) and its complications, and they are inseparably linked as each begets and ampliies the other. Although pathways involved in intrarenal ROS production and inlammation in experimental CKD have been widely explored, the relationship of DN on proinlammatory cytokines and Nrf2-Keap1 system in diabetes is poorly studied [27,28,30].…”