The kidney plays a key role in the control of body fluid volume and composition, and tubular and/or hemodynamic dysfunction are common features of diseases such as hypertension and diabetes. The renal P450 arachidonic acid (AA) monooxygenase biosynthesizes hydroxy- and epoxy-AA derivatives that are known to modulate tubular transport and vascular reactivity. Animal models of P450 gene dysfunction confirmed the physiological importance of these enzymes, characterized their pathophysiological roles, and provided insights into the mechanism of action of their metabolites. Studies of the pathophysiological roles of human P450s identified associations between P450 gene variants with hypertension, the progression of renal disease, and with components of metabolic syndrome. This application proposes to build upon these studies and to address: a) mechanisms by which the P450-eicosanoids regulate renal tubular transport and vascular reactivity, b) the role of P450s in human hypertension and renal complications of diabetes, and c) the molecular basis of these pathophysiological roles. To achieve these goals, we developed a multidisciplinary approach for studies of P450-isoform specific phenotypes at the cellular, organ and whole animal levels, the analysis of associations between alterations in human P450 gene structure/expression and disease, and for clinical studies of their metabolic and functional consequences. Cyp2c and Cyp4a knockout mice will be used to study gene-dependent changes in: a) renal EET and/or 20-HETE synthase expression, b) tubular transport and/or vascular reactivity, and c) systemic blood pressure and the progression of renal disease. Associations between CYP2C8/2C9 or CYP4A11 genotypes with blood pressure, insulin sensitivity, and urine and plasma EET and 20-HETE levels will be explored to define pathophysiological correlations between variant alleles, AA epoxidation/hydroxylation, and individual responses to changes in dietary salt intake, the administration of diuretics, or peroxisomal proliferator activated receptor (alpha) ligands. Our long term goals are to provide a molecular understanding of role(s) of P450 eicosanoids in renal physiological, their mechanism and site of action, and relevance to human disease. These are needed for the development of meaningful approaches for: a) the unequivocal definition of human pathophysiological significance, and b) future pharmacological targeting, and clinical diagnosis and intervention.
Hypertension and diabetes are leading causes of cardiovascular, cerebral, and renal disease morbidity and mortality, and their prevalence and multiple medical and socio-economic consequences make them a major health challenge. It is expected that the definition of a role for kidney P450s in human hypertension and diabetes will lead to new approaches for the early diagnosis and treatment of these diseases, and contribute to prevent their devastating consequences.
|Elijovich, Fernando; Milne, Ginger L; Brown, Nancy J et al. (2018) Two Pools of Epoxyeicosatrienoic Acids in Humans: Alterations in Salt-Sensitive Normotensive Subjects. Hypertension 71:346-355|
|Sausville, Lindsay N; Gangadhariah, Mahesha H; Chiusa, Manuel et al. (2018) The Cytochrome P450 Slow Metabolizers CYP2C9*2 and CYP2C9*3 Directly Regulate Tumorigenesis via Reduced Epoxyeicosatrienoic Acid Production. Cancer Res 78:4865-4877|
|Garcia, Victor; Gilani, Ankit; Shkolnik, Brian et al. (2017) 20-HETE Signals Through G-Protein-Coupled Receptor GPR75 (Gq) to Affect Vascular Function and Trigger Hypertension. Circ Res 120:1776-1788|
|Guo, Zhijun; Sevrioukova, Irina F; Denisov, Ilia G et al. (2017) Heme Binding Biguanides Target Cytochrome P450-Dependent Cancer Cell Mitochondria. Cell Chem Biol 24:1259-1275.e6|
|Zhang, Hui; Falck, John R; Roman, Richard J et al. (2017) Upregulation of 20-HETE Synthetic Cytochrome P450 Isoforms by Oxygen-Glucose Deprivation in Cortical Neurons. Cell Mol Neurobiol 37:1279-1286|
|Gangadhariah, Mahesha H; Dieckmann, Blake W; Lantier, Louise et al. (2017) Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans. Diabetologia 60:1066-1075|
|Shuey, Megan M; Billings 4th, Frederic T; Wei, Shouzou et al. (2017) Association of gain-of-function EPHX2 polymorphism Lys55Arg with acute kidney injury following cardiac surgery. PLoS One 12:e0175292|
|Fan, Fan; Pabbidi, Mallikarjuna R; Ge, Ying et al. (2017) Knockdown of Add3 impairs the myogenic response of renal afferent arterioles and middle cerebral arteries. Am J Physiol Renal Physiol 312:F971-F981|
|Agarwal, Anupam; Dong, Zheng; Harris, Raymond et al. (2016) Cellular and Molecular Mechanisms of AKI. J Am Soc Nephrol 27:1288-99|
|Chen, Li; Joseph, Gregory; Zhang, Frank F et al. (2016) 20-HETE contributes to ischemia-induced angiogenesis. Vascul Pharmacol 83:57-65|
Showing the most recent 10 out of 376 publications