Pancreatic Polypeptide-Fold Peptide Receptors and Angiotensin II–Induced Renal Vasoconstriction

Abstract

Abstract-TheKey Words: receptors Ⅲ neuropeptides Ⅲ peptides Ⅲ hypertension T he renin-angiotensin system (RAS) is essential for the development and maintenance of genetic hypertension in spontaneously hypertensive rats (SHRs). 1,2 Moreover, transplantation studies reveal that, in addition to the RAS, the SHR kidney is pivotal to the pathophysiology of hypertension in the SHR. 3,4 Finally, the renal sympathetic nervous system also appears to importantly contribute to the pathophysiology of hypertension in SHRs. In support of this latter concept, chronic denervation of the SHR kidney both delays the development of hypertension and attenuates the maximum increase in blood pressure in SHR. [5][6][7][8] Thus, there appears to be a coinvolvement of the RAS, the sympathetic nervous system, and the kidney in SHR hypertension.Many studies have been performed in search of a possible explanation for the coinvolvement of the RAS and the kidney in SHR hypertension. In this regard, studies do not support an increased expression of renal angiotensin II (Ang II) receptors 9 or increased levels of circulating 10 or renal 11 Ang II; also, SHRs do not have altered renal Ang II degradation rates. 12 However, SHRs do exhibit increased renovascular responses to Ang II, 13,14 and this appears to be the explanation for the coinvolvement of the RAS and the kidney in SHR hypertension.Our previous research indicates that G i mediates, in part, the enhanced renovascular response to Ang II in SHR. For example, pertussis toxin, an inhibitor of G i , abolishes the increased renovascular response to Ang II in SHR. 15,16 Importantly, activation of renal sympathetic nerves leads to the release of neuropeptide Y (NPY). 17 NPY is an example of a pancreatic polypeptide (PP)-fold peptide, 18 and NPY binds with high affinity to Y 1 , Y 2 ,

Endogenous adenosine contributes to renal sympathetic neurotransmission via postjunctional A1receptor-mediated coincident signaling

“…Since both NE and angiotensin II signal via Gq-coupled receptors [␣ 1 -adrenoceptors (9) and angiotensin II AT 1 receptors (44), respectively], the A 1 receptor would also likely enhance NEinduced renal vasoconstriction. Also, A 1 receptors are Gicoupled receptors (49), and studies by our lab demonstrate coincident signaling between Gq-coupled receptors (for example, AT 1 receptors and vasopressinV 1 receptors) and Gi-coupled receptors (for example, Y 1 receptors and ␣ 2 -adrenoceptors) in the renal microcirculation resulting in potentiation of Gq-induced renal vasoconstriction by the Gi signal transduction pathway (10,11,17). Thus, taken together, this line of reasoning would predict coincident signaling in the renal microcirculation between released adenosine, via A 1 receptorinduced activation of Gi, and released NE, via ␣ 1 -adrenoceptorinduced activation of Gq.…”

Sitagliptin Augments Sympathetic Enhancement of the Renovascular Effects of Angiotensin II in Genetic Hypertension

“…1 In contrast, kidneys from normotensive WistarKyoto rats (WKY) are resistant to this interaction. 1 Our studies also show that unlike Y 1 Rs, renovascular Y 2 receptors (Y 2 Rs) exert little effect on Ang II-induced renovascular responses in kidneys from either SHR or WKY.…”

“…1 In contrast, kidneys from normotensive WistarKyoto rats (WKY) are resistant to this interaction. 1 Our studies also show that unlike Y 1 Rs, renovascular Y 2 receptors (Y 2 Rs) exert little effect on Ang II-induced renovascular responses in kidneys from either SHR or WKY. 1 Although we do not know precisely why SHR, but not WKY, kidneys are susceptible to Y 1 R-induced enhancement of Ang IImediated renal vasoconstriction, these findings indicate that endogenous agonists of Y 1 Rs, but not Y 2 Rs, would potentiate Ang II-induced renal vasoconstriction in geneticallysusceptible kidneys, provided Y 1 R agonists reach the renal microcirculation.…”

“…It is conceivable, however, that renal dipeptidyl peptidase IV (DPP IV, also called CD26) limits stimulation of renal Y 1 Rs by physiological processes that increase the exposure of the renal microcirculation to PYY and NPY . DPP IV is an ecto-enzyme that is anchored to the cell surface and converts PYY to PYY 12 and NPY to NPY 3-36 12 by cleaving 2 amino acids from the N terminus of PYY and NPY .…”

Role of RACK1 in the differential proliferative effects of neuropeptide Y1–36 and peptide YY1–36 in SHR vs. WKY preglomerular vascular smooth muscle cells

“…Our previously published work demonstrates that Y 1 receptor expression is not different in preglomerular microvessels from SHR vs. WKY (15), so receptor expression differences are unlikely to account for the differential proliferative responses of SHR vs. WKY to NPY and PYY . On the other hand, our previously published work does show that signaling via G i -linked receptors is enhanced in the renal vasculature of SHR vs. WKY (15).…”