Study of the role of angiotensin fragments in renal hemodynamics and sodium excretion

Project Details

Description

The renin-angiotensin system (RAS) is widely recognized as the most powerful signaling system controlling sodium balance, body fluid volume and arterial blood pressure. Angiotensin (Ang) II is well-known for its vasoconstrictor, growth-promoting and endocrine (stimulation of the release of aldosterone and vasopressin) properties, which regulate many aspects of the renal function and thereby influence blood pressure. Ang II mediates its functions through stimulation of two pharmacologically distinct receptors, the Ang II receptor type 1 (AT1) and type 2 (AT2) whereas two subtypes, called AT1a and AT1b, have been identified for the rodent AT1 receptors, but not in humans. AT2 receptor stimulation was shown to oppose the effects of AT1 receptor activation in some studies.
Ang II is metabolized to Ang III (Arg-Val-Tyr-lle-His-Pro-Phe) by aminopeptidase A (APA). In turn, aminopeptidase N (APN) metabolizes Ang III to Ang IV (Val-Tyr-IIe-His-Pro-Phe) and, along with dipeptidylaminopeptidase (DAP), degrades Ang IV. High affinity binding sites for Ang IV were characterized and denoted as "AT4 receptors". In the rat kidney, autoradiographic studies demonstrated the presence of AT4 binding sites in the apical membrane and cell body of proximal convoluted and straight tubules within the cortex and outer stripe of the outer medulla. Recent findings suggest important physiological actions for Ang IV in the field of cardiovascular and renal function (depressor effect, renal vasodilatation and natriuresis) but contradicting data have been published. However, there is evidence that the AT4 binding sites correspond to the membrane-associated insulin-regulated aminopeptidase (IRAP).

Ang A (Ala-Arg-Val-Tyr-Ile-His-Pro-Phe) is a novel human strong vasoconstrictive angiotensin-derived peptide, most likely generated by enzymatic transformation through mononuclear leukocyte-derived aspartate decarboxylase. Ang A has the same affinity to the AT1 receptor as Ang II, but a higher affinity to the AT2 receptor. Plasma Ang A concentration is increased in end-stage renal failure. Because of its stronger agonism at the AT2 receptor, Ang A may modulate the harmful effects of Ang II.

The aims of this study are 1). To explore the role and mechanism of action of Ang IV in blood pressure, renal hemodynamics and renal sodium excretion using ligands such as Ang IV itself, AT4-16 (a more stable Ang IV analogue), LVV-Hemorphin-7 (an endogenous agonist). 2). To study the effect of Ang A on blood pressure, renal hemodynamics and renal sodium excretion, the possible role of Ang A in the pathogenesis of the renal failure will also be studied. 3). To reveal which receptor is involved in response to Ang IV and Ang A in the regulation of blood pressure and renal hemodynamics by using AT1a, AT1b, AT2, and IRAP/ AT4 receptor knockout mice.
AcronymOZR2001
StatusFinished
Effective start/end date1/11/0930/04/10

Keywords

  • Pituitary Tumors
  • Gene Regulation
  • IGF-1
  • Hypophyse
  • Prolactin
  • PRL-R signalling pathways
  • In Situ Hybridization
  • Lymphohemopoietic System
  • Dopamine
  • Endocrinology
  • PRL isoforms
  • PRL gene regulation
  • termination of signalling
  • CIS and SOCS molecules
  • PRL-R pathways
  • PRL
  • Growth Hormone

Flemish discipline codes

  • Basic sciences
  • Biological sciences