Abstract
Over 10% of the global population suffers from kidney disease. However, only kidney replacement therapies, which burden medical expenses, are currently effective in treating kidney disease. Therefore, elucidating the complicated molecular pathology of kidney disease is an urgent priority for developing innovative therapeutics for kidney disease. Recent studies demonstrated that intertwined renal vasculature often causes ischemia-reperfusion injury (IRI), which generates oxidative stress, and that the accumulation of oxidative stress is a common pathway underlying various types of kidney disease. We reported that activating the antioxidative transcription factor Nrf2 in renal tubules in mice with renal IRI effectively mitigates tubular damage and interstitial fibrosis by inducing the expression of genes related to cytoprotection against oxidative stress. Additionally, since the kidney performs multiple functions beyond blood purification, renoprotection by Nrf2 activation is anticipated to lead to various benefits. Indeed, our experiments indicated the possibility that Nrf2 activation mitigates anemia, which is caused by impaired production of the erythroid growth factor erythropoietin from injured kidneys, and moderates organ damage worsened by anemic hypoxia. Clinical trials investigating Nrf2-activating compounds in kidney disease patients are ongoing, and beneficial effects are being obtained. Thus, Nrf2 activators are expected to emerge as first-in-class innovative medicine for kidney disease treatment.
Highlights
The kidneys are two organs located in the retroperitoneal space and function to purify blood and to control blood pressure by producing the vasopressor renin, to maintain bone mineral homeostasis by activating vitamin D, and to produce the erythroid growth factor erythropoietin (Epo)
Patients suffering from acute kidney injury (AKI) bear a heightened risk of disease progression to chronic kidney disease (CKD) followed by end-stage renal disease (ESRD), which is the final common clinical feature of renal failure [9]
In 2015, a phase II randomized double-blind, placebo-controlled clinical trial of CDDO-ME was restarted with 120 CKD patients of Grade 3 or 4, excluding patients bearing risk factors for fluid overload, and the results nicely showed a significant increase in estimated glomerular filtration rate (eGFR) without any signs of fluid overload (TSUBAKI study; Table 3) [17,18]
Summary
The kidneys are two organs located in the retroperitoneal space and function to purify blood and to control blood pressure by producing the vasopressor renin, to maintain bone mineral homeostasis by activating vitamin D, and to produce the erythroid growth factor erythropoietin (Epo). Among the different types of renal failure, acute kidney injury (AKI) [3] and chronic kidney disease (CKD) are the major syndromes [4]. Patients suffering from AKI bear a heightened risk of disease progression to CKD followed by end-stage renal disease (ESRD), which is the final common clinical feature of renal failure [9]. On the other hand, considering that AKI and CKD interact with each other, it is known that patients with CKD bear a higher risk of developing AKI [11]. For kidney functions such as reabsorption and humoral factor secretion, kidneys are rich in capillaries compared with other organs. We introduce the molecular functions of Keap and Nrf in kidney disease as well as up-to-date information on the development of drugs targeting the Keap1–Nrf system for kidney disease treatment
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