Reno-protective mechanisms of EETs in acute and chronic obstructive nephropathy

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Abstract/Project Summary Ureteral obstruction is a common cause of acute and chronic kidney disease and may result from a wide variety of pathologic processes, intrinsic and extrinsic to the urinary system. Congenital obstructive anomalies of the urinary tract are the most common cause of chronic kidney disease (CKD) and end stage renal disease (ESRD) in children. In adults, obstructive uropathy accounts for 10% of the causes of acute renal failure and 4% of the cases of end stage renal disease. Tubulointerstitial fibrosis is the final common pathway that leads to disease progression and end-stage renal disease. Great strides in our understanding of renal tubulointerstitial fibrosis, particularly as to how inflammation, fibroblast activation, tubular and microvascular injury contribute to fibrogenesis, have been accomplished in the past decade. However, treating fibrotic diseases has been challenging because of the complex pathogenesis of the disease. Identification of the primary signals or the core pathway that is essential to convert an initial stimulus to the development of fibrosis, and their targeting may be required to limit disease progression. Our published data indicate the novel paradigm that epoxyeicosatrienoic acids (EETs) stimulation can completely prevent fibrosis and inflammation in obstructive nephropathy models. The overall project goal is to elucidate the mechanisms by which EETs prevent renal fibrogenesis and determine the translational potential of EET activation or augmenting its signaling pathways. Based on preliminary data, our central hypothesis is that EETs produced in the kidney after UUO and in the clinically relevant chronic obstructive nephropathy and release models prevent poly (ADP-ribose) polymerase 1 (PARP1)-mediated activation of TLR4, NF-κB, TNF-α, interleukin (IL) 1, 2, 6 and 12 and leukocyte adhesion molecules. Further, our data indicate that EETs regioisomers down-regulate p53 expression. Our novel data indicate that p53 inhibition promotes fatty acid oxidation (FAO) and prevents intracellular lipid accumulation to prevent fibrosis after UUO. Defects in FAO and intracellular lipid accumulation are observed in UUO and other CKD models and has an important role in oxidative stress, inflammation, cell death, phenotypes observed in fibrogenesis and CKD. It should be emphasized that a role for p53 in FAO or lipid accumulation has not been reported in any tissue or disease state and is paradigm shifting in CKD research. We will determine the mechanism by which p53 regulates fatty acid oxidation in ureteral obstruction models. Our studies are innovative as a role for EETs signaling as a primary mechanism instigating renal fibrogenesis has not been reported. Understanding the molecular mechanisms of fibrogenesis will have wide implications as they may provide the basis for designing novel therapeutic strategies, to prevent fibrotic diseases not only in the kidney but also in other organs including the liver and heart.