Diabetes and hypertension are the leading causes of endstage renal disease (ESRD). Despite effective medications, the incidence of ESRD is increasing and the associated costs now exceed $15 billion a year. The renal expression of TGF-beta is elevated in hypertension and diabetes and blockade of this pathway decreases renal fibrosis. However, the factors that increase the production of TGF-beta and its role in the initiation of renal disease remain to be determined. In preliminary experiments, we found that inducing the renal formation of 20-HETE or blocking the actions of TGF-beta attenuate the development of renal disease in Dahl S rats. TGF-beta also directly increased the permeability of glomeruli to albumin (Palb) and inhibited the glomerular formation of 20-HETE. Thus, this proposal will evaluate the hypothesis that a deficiency in the renal formation of 20-HETE leads to elevations in glomerular capillary pressure (Pgc) and the renal expression of TGF-beta in Dahl S rats and that the increase in TGF-beta triggers the development of proteinuria and renal disease by increasing Palb.
Specific Aim 1 will determine the relationships between Pgc, the renal expression of TGF-beta, Palb and the development of renal disease and the effects of servocontrol of renal perfusion pressure (RPP) on these responses.
Specific Aim 2 will determine if the reduced production of 20-HETE contributes to the increases in Pgc, TGF-beta and the development of renal disease.
Specific Aim 3 will examine the interactions between TGF-beta and 20-HETE in the regulation of Palb and the mechanism by which TGF-beta inhibits the formation of 20-HETE.
Specific Aim 4 will determine whether Palb is altered early in the development of hypertension and the role of TGF-beta in mediating this response. These studies will employ an array of techniques, ranging from direct measurement of Pgc, LC/MS measurement of 20-HETE and chronic servocontrol of RPP to measurements of Palb and Ca++ in isolated glomeruli. They will also utilize a newly-developed congenic strain of Dahl S rats in which renal 20-HETE levels are elevated and novel inhibitors and antibodies that can manipulate the 20-HETE and TGF-beta pathways in vivo. These translational studies will provide important new information on the role of TGF-beta, 20-HETE and Pgc in the pathogenesis of hypertension-induced renal disease and may be applicable to diabetes and other models of renal disease as well in which TGF-beta and Pgc are also elevated.
|Ge, Ying; Murphy, Sydney R; Fan, Fan et al. (2014) Role of 20-HETE in the impaired myogenic and TGF responses of the Af-Art of Dahl salt-sensitive rats. Am J Physiol Renal Physiol 307:F509-15|
|Pabbidi, Mallikarjuna R; Mazur, Olga; Fan, Fan et al. (2014) Enhanced large conductance K+ channel activity contributes to the impaired myogenic response in the cerebral vasculature of Fawn Hooded Hypertensive rats. Am J Physiol Heart Circ Physiol 306:H989-H1000|
|Burke, Marilyn; Pabbidi, Mallikarjuna R; Farley, Jerry et al. (2014) Molecular mechanisms of renal blood flow autoregulation. Curr Vasc Pharmacol 12:845-58|
|Maranon, Rodrigo O; Lima, Roberta; Mathbout, Mohammed et al. (2014) Postmenopausal hypertension: role of the sympathetic nervous system in an animal model. Am J Physiol Regul Integr Comp Physiol 306:R248-56|
|Ge, Ying; Murphy, Sydney R; Lu, Yan et al. (2013) Endogenously produced 20-HETE modulates myogenic and TGF response in microperfused afferent arterioles. Prostaglandins Other Lipid Mediat 102-103:42-8|
|Pabbidi, Mallikarjuna R; Juncos, Julio; Juncos, Luis et al. (2013) Identification of a region of rat chromosome 1 that impairs the myogenic response and autoregulation of cerebral blood flow in fawn-hooded hypertensive rats. Am J Physiol Heart Circ Physiol 304:H311-7|
|Kojima, Naoki; Williams, Jan M; Takahashi, Teisuke et al. (2013) Effects of a new SGLT2 inhibitor, luseogliflozin, on diabetic nephropathy in T2DN rats. J Pharmacol Exp Ther 345:464-72|
|Chen, Chun Cheng Andy; Geurts, Aron M; Jacob, Howard J et al. (2013) Heterozygous knockout of transforming growth factor-?1 protects Dahl S rats against high salt-induced renal injury. Physiol Genomics 45:110-8|
|Orozco, Ludwig D; Liu, Huiling; Perkins, Eddie et al. (2013) 20-Hydroxyeicosatetraenoic acid inhibition attenuates balloon injury-induced neointima formation and vascular remodeling in rat carotid arteries. J Pharmacol Exp Ther 346:67-74|
|Slaughter, Tiffani N; Paige, Adrienne; Spires, Denisha et al. (2013) Characterization of the development of renal injury in Type-1 diabetic Dahl salt-sensitive rats. Am J Physiol Regul Integr Comp Physiol 305:R727-34|
Showing the most recent 10 out of 137 publications