We have recently discovered that loss of organic anion transporter 3 (OAT3), but not loss of the related renal transporters OAT1 and RST (URAT1), results in decreased blood pressure in mice. This suggests that an endogenous compound(s) specifically transported by OAT3 is involved in the regulation of blood pressure, and our preliminary data indicate that both renal and vascular mechanisms may contribute. We propose in Specific Aim 1 to investigate the potential renal mechanisms. OAT3 is expressed in the renal proximal tubule, distal tubule, and collecting duct, and its endogenous substrates include suppressors of tubular NaCl transport such as PGE2. Moreover, preliminary studies show that the non-selective OAT inhibitor, probenecid, lowers the activity of the epithelial sodium channel, ENaC, in the collecting duct, and Oat3 knockout (-/-) mice manifest significantly greater weight loss in response to a low NaCl diet. These data suggest that OAT3 may contribute to upregulation of renal NaCl reabsorption and thereby to blood pressure regulation. We will perform renal cross-transplantation to differentiate roles of renal versus extra-renal OAT3, and determine differences between Oat3-/- and wild-type (+/+) mice in renal NaCl transport, ENaC activity, and the role of PGE2, so as to identify sites of impaired NaCl reabsorption and/or altered regulation.
In Specific Aim 2, we will investigate potential vascular mechanisms underlying blood pressure regulation by OAT3. We previously identified thymidine as a novel endogenous OAT3 substrate that accumulates in the plasma of Oat3-/- mice and acutely lowers blood pressure. We now propose to assess vascular tone in Oat3-/- and +/+ mice, and to determine effects of thymidine and other potentially vasoactive OAT3 substrates, including PGE2 and cGMP. Finally, since loss of OAT3 results in decreased blood pressure, pharmacological inhibition of OAT3 function might also decrease blood pressure, raising the possibility of a novel approach to the design of antihypertensive drugs. Preliminary data show that administration of non-selective OAT inhibitors can reduce blood pressure in mice with both normal and increased blood pressure. We propose in Specific Aim 3 to screen for selective OAT3 inhibitors as a means to identify novel compounds with antihypertensive potential. Specifically, we will first identify OAT3 inhibitors via iterative in silico and in vitro steps (characterize an initial set of inhibitors to generate a pharmacophore;use the pharmacophore to perform in silico screens of large chemical structure databases;test high-scoring matches from these screens for OAT3 inhibition in vitro). We will then test the most potent of the identified inhibitors for antihypertensive capacity in vivo. We provide preliminary data indicating the feasibility of these Aims (including identification of selective OAT3 inhibitors), and have enlisted the support of expert collaborators. The proposed work thus has the potential to significantly increase our understanding of mechanisms of blood pressure regulation and to thereby impact the medical treatment of hypertension.
We have discovered that loss of a specific kidney protein (OAT3) or blocking of its function can lead to decreased blood pressure. We plan to investigate how OAT3 controls blood pressure, which could lead to a better understanding of how high blood pressure (hypertension) develops. We will also identify selective OAT3- blocking substances and explore their ability to reduce blood pressure - such substances could potentially be useful in the treatment of patients with hypertension.
|Fu, Yiling; Gerasimova, Maria; Batz, Falk et al. (2015) PPAR? agonist-induced fluid retention depends on ?ENaC expression in connecting tubules. Nephron 129:68-74|
|Edwards, Aurélie; Castrop, Hayo; Laghmani, Kamel et al. (2014) Effects of NKCC2 isoform regulation on NaCl transport in thick ascending limb and macula densa: a modeling study. Am J Physiol Renal Physiol 307:F137-46|
|Vallon, Volker (2014) Do tubular changes in the diabetic kidney affect the susceptibility to acute kidney injury? Nephron Clin Pract 127:133-8|
|Eraly, Satish A; Nievergelt, Caroline M; Maihofer, Adam X et al. (2014) Assessment of plasma C-reactive protein as a biomarker of posttraumatic stress disorder risk. JAMA Psychiatry 71:423-31|
|Kumar, Rajiv; Vallon, Volker (2014) Reduced renal calcium excretion in the absence of sclerostin expression: evidence for a novel calcium-regulating bone kidney axis. J Am Soc Nephrol 25:2159-68|
|Vallon, Volker; Docherty, Neil G (2014) Intestinal regulation of urinary sodium excretion and the pathophysiology of diabetic kidney disease: a focus on glucagon-like peptide 1 and dipeptidyl peptidase 4. Exp Physiol 99:1140-5|
|Vallon, Volker; Gerasimova, Maria; Rose, Michael A et al. (2014) SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol 306:F194-204|
|Rieg, Timo; Masuda, Takahiro; Gerasimova, Maria et al. (2014) Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am J Physiol Renal Physiol 306:F188-93|
|Fu, Yiling; Vallon, Volker (2014) Mineralocorticoid-induced sodium appetite and renal salt retention: evidence for common signaling and effector mechanisms. Nephron Physiol 128:8-16|
|Masuda, Takahiro; Fu, Yiling; Eguchi, Akiko et al. (2014) Dipeptidyl peptidase IV inhibitor lowers PPARýý agonist-induced body weight gain by affecting food intake, fat mass, and beige/brown fat but not fluid retention. Am J Physiol Endocrinol Metab 306:E388-98|
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