The chronic kidney disease (CKD) of aging affects more than 20 million US citizens, is increasing in incidence as the population ages, and is a major contributor to heart disease. We showed that advanced glycation endproducts (AGEs) can cause CKD by inducing inflammation and increased oxidative injury. Since AGEs accumulate in aging, they may underlie the chronic kidney disease (CKD) of aging. Two AGE receptors, AGER1 and RAGE were thought to be the main modulators of AGE-induced responses. While AGER1 detoxifies AGEs and modulates oxidant stress, RAGE promotes oxidative stress and organ failure. We now find that TLR4 also mediates AGE-induced responses, in particular the induction of inflammatory cytokines and subsequent renal fibrosis. The levels of these receptors change in aging: AGER1 levels decrease, RAGE does not change but TLR4 levels increase. The net result is an increase in AGE-induced inflammatory responses in aging, largely due to increased AGE levels which accompany aging. However, mice lacking functional TLR4, do not develop the CKD of aging. Thus, we hypothesize that AGEs signaling through TLR4 significantly contributes to the CKD of aging. The CKD of aging contributes to other aging-related diseases, since the kidney is the major site for the excretion of these toxic AGEs. Therefore, as kidney function declines with """"""""normal"""""""" aging, AGEs would continue to accumulate, causing inflammation and oxidant stress. As the kidneys are both the target of AGE-induced inflammation and the main site of AGE excretion, a vicious cycle would result in which kidney function progressively decreases, rendering them increasingly unable to handle toxic AGEs. Thus, it is critical to define the mechanisms of TLR4 activation by AGEs, to elucidate the nature of the AGE ligands which bind TLR4, and to develop interventions which target specific molecules that retard the loss of kidney function in aging. Elucidation of the molecular basis of AGE-induced TLR4 activation may identify strategies to decrease the CKD of aging. We propose to 1) Determine if interference with key TLR4 signaling molecules will reduce or prevent the CKD of aging, 2) Determine the molecular basis of TLR4 activation by AGEs, 3) Determine whether AGE-stimulated TLR4 activation contributes to the CKD of aging by inducing the expression of inflammatory molecules in glomerular and proximal tubular cells, and 4) Determine if TLR4 is involved in AGE- stimulated inflammatory responses in proximal tubules in vivo.
The chronic kidney disease of aging affects more than 20 million adults in the United States and is a major contributor to cardiovascular diseases. Our data suggests that TLR4 contributes to this condition. Since TLR4 activation may be manageable with currently available drugs and interventions, our investigations may provide new avenues to treat this disease.
