Inhibition of inflammatory cytokines - potential new treatment for diabetic nephropathy
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Type II diabetes mellitus is currently on the rise and reaching epidemic proportions in the United States. In addition to this increase, the number of cases of diabetic complication such as kidney disease has increased. Currently diabetic kidney disease is the leading cause for end stage renal disease in the United States accounting for nearly half of all cases. Type II diabetes is the result of metabolic, hemodynamic and inflammatory alterations within the body. Currently there is a standard of care to treat both metabolic and hemodynamic perturbations by enforcing tight glycemic control and utilizing anti-hypertensive drugs, most notably RAS inhibitors. These therapeutic interventions however, are not sufficient as many patients with type II diabetes will still develop diabetic kidney disease therefore another treatment option is imperative. Currently there are no treatments available to counteract the adverse inflammatory responses associated with type II diabetes which are strong contributors to the progression of the diabetic kidney disease. Among the inflammatory parameters studied as potential targets for therapeutic intervention the inflammatory cytokine tumor necrosis factor-α (TNF-α) stands out among the rest for its multifaceted role in disease progression. TNF-α has been shown to both directly and indirectly involved in development and progression of diabetic kidney disease. The inflammatory cytokine itself is toxic to renal cells initially increasing the permeability of the glomerular filtration barrier and contributing to proteinuria which eventually causes cellular apoptosis. TNF-α also activates second messengers and up-regulates transcription factors that further contribute to the progression of diabetic kidney disease. Two TNF-α inhibitors, pentoxifylline and chrysin have stood out among the other investigational drugs which have been studied as potential therapeutic options to delay the progression of diabetic kidney disease. Pentoxifylline is a methyl-xanthine derivative that is currently used to treat peripheral vascular disease. It has shown good effect in clinical trials decreasing both urinary TNF-α concentrations as well as urinary protein excretion. Chrysin is a natural plant derivative belonging to the flavonoid family and is known for its anti-inflammatory and anti-oxidant properties. Currently chrysin has only been studied in animal models of diabetic kidney disease but has shown to not only decrease concentrations of inflammatory cytokines to control levels and improve renal functions but also prevented the histopathological changes associated with diabetic kidney disease suggesting that chrysin has the ability to not only slow the progression of disease and preserve renal function, it has the ability to prevent the disease from ever taking root. Diabetic kidney disease is a devastating disease affecting millions of people worldwide. It is important for further investigation with these investigational drugs to be performed in large scale clinical trials to produce safety and efficacy data with the end goal of becoming approved as new treatments for diabetic kidney disease.