Release date: 2014-12-05
Chronic kidney disease (CKD) affects at least a quarter of Americans over the age of 60 and significantly reduces life expectancy. However, there are not many drugs available for the treatment of CKD, which can only moderately delay the disease and inhibit its transformation into renal failure.
Now, however, researchers at the University of Pennsylvania have found an aspect of CKD development and point to a promising new treatment strategy. Studies have found that energy production defects in kidney cells affected by CKD play a key role in the development of CKD. Katalin Susztak, MD, said: Restoring the energy supply in these cells can largely prevent signs of CKD in mouse models. . The study was published in the journal Nature Medicine, and Susztak and his colleagues focused on the core features of CKD: the fibrosis process. Fibrosis is a pathological response to chronic kidney stress, including abnormal accumulation of fibrotic collagen, loss of capillaries, death of tubular epithelial cells one by one, and decreased ability of the kidney to properly filter blood.
The researchers compared gene activity patterns in fibrotic kidney tissue samples and normal human kidney tissue samples. They found that abnormal patterns of gene networks are associated with a sharp decline in renal inflammation and the activity of gene networks that regulate energy metabolism in fibrotic kidney samples. In fact, inflammation is a factor in CKD that is well known, so Susztak and her colleagues are targeting two types of energy metabolism: glucose oxidation and fatty acid oxidation, both of which appear to be significantly reduced in fibrotic samples.
Susztak said: We found that in the normal supply of energy, renal tubular epithelial cells preferentially use fatty acid oxidation. Even when fatty acid metabolism declines in the case of CKD, these cells do not switch to burning glucose to generate energy. The Susztak team studied a mouse model of renal fibrosis and again found that the gene activity that regulates fatty acid metabolism is low.
In the mouse model, a decrease in fatty acid metabolism occurs before signs of fibrosis. In human renal tubular epithelial cells, artificially reducing fatty acid metabolism can rapidly lead to fibrotic symptoms, including accumulation of fat molecules and death of many affected cells. Renal cell fat accumulation has been postulated to cause significant cell death in CKD fibrosis. However, Susztak's mouse model of renal tubular epithelial fat accumulation showed that fat accumulation had minimal effect on renal tubular epithelial cells themselves, and when fatty acid metabolism decreased, a more important factor in fibrosis was the loss of energy in the cells.
The researchers also found evidence that the closure of fatty acid metabolism in renal tubular epithelial cells is largely caused by the growth factor TGFβ. TGFβ is known to promote fibrosis and has been associated with high blood sugar levels, hypertension and inflammation, high blood sugar levels, hypertension and inflammation as triggers for CKD.
Encouragingly, when the Susztak team used genetic technology or active compounds that enhance fatty acid metabolism genes to restore fatty acid metabolism in a mouse model of kidney fibrosis, it prevented almost all signs of fibrosis. The test compound fenofibrate is an existing anti-cholesterol drug that activates PPARA, a key gene in fatty acid metabolism. But when used as a kidney disease drug has side effects. We hope to develop new compounds similar to fenofibrate or to boost enzymes that are specifically involved in fatty acid metabolism, so that we may be able to significantly delay the progression of CKD. She and her colleagues also attempted to link new changes in CKD fibrosis to epigenetic changes.
Source: Bio Valley
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