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• Properties

  Mr. 38 kDa. Renin has high specificity on AGT and cleaves Ang I from AGT. The cleavage specificity is determined by the [HPF]-domain on Ang I. Renin recognizes this signature domain and cleaves the peptide bond at two aa residues after the domain. The [HPF]-domain is highly conserved among vertebrates (see Angiotensin II), indicating that similar functional constraints could be present in other vertebrate renins. Renin can be activated by proteolysis, acidic pH, and low temperature.;

• Gene, mRNA, and mRNA

  REN1 is located at chromosome 1q32.1 in humans. Renin is synthesized as an inactive form called prorenin but recent studies indicated that prorenin can bind to the renin receptor and activate the cleavage site reversibly by changing the conformation of the prosegment. REN1 is synthesized mainly by the kidney but mRNA is also found in many other tissues, including the heart, brain, and adrenal glands.;

• Synthesis and release

  The macula densa, in response to the change in the Na concentration in the distal tubules, signals the juxtaglomerular cells to release renin. Renin is stored in granules and the secretion is stimulated by the β-adrenergic response and cAMP augmentation. The release of active renin from the kidney is inhibited by increased arterial pressure or Ang II, and an increased intracellular Ca concentration. This is in contrast to the other secretory cells, in which an increase in intracellular calcium usually enhances the depletion of secretory granules. Thus, this is often called the calcium paradox. The regulatory elements of the promoter of the renin gene were termed the “renin enhancer.” This was later found to be a compound regulatory element with several stimulatory and inhibitory activities. In the renin enhancer, cAMP response elements have been identified. Besides transcriptional regulation, a posttranslational regulation at the untranslated region (a 200 bp segment beyond the coding region) was also known, where the mRNA stability can be enhanced by cAMP stimulation.;

• Receptors

  The renin receptor (ATP6AP2) binds to both prorenin and renin. The renin receptor gene is located on chromosome Xp11. in humans. The major known function is that the binding increases the catalytic activity of renin on AGT by 5–10 fold: the Km for AGT (in the absence of the renin receptor) is 1μM and the Km of the membrane-bound renin receptor complex is 0.15μM. The renin receptor is abundantly expressed in the heart, brain, and placenta, and lower expressions are found in the kidney and liver. In the brain, the renin receptor is expressed in the subfornical organ, paraventricular nucleus, supraoptic nucleus, tractus solitaries nucleus, and rostral ventrolateral medulla, which are likely involved in the regulation of cardiovascular and volume regulation. Global knockout of the renin receptor is embryonically lethal. Genome data also suggest that the orthologous renin receptor is present in other vertebrates, including teleosts and tetrapods.;

• Antagonist

  Aliskiren is the first in a new class of orally active, nonpeptide, low-molecular-weight renin inhibitors. It is a transition-state mimetic with favorable physicochemical properties, including high aqueous solubility (350mg/mL at pH 7.4) and high hydrophilicity (log Poct/water=2.45 at pH 7.4), which are important properties for oral bioavailability. Aliskiren is designed through a combination of molecular modeling techniques and crystal structure elucidation, and it effectively reduces the blood pressure as a monotherapy as well in combination therapy.;

• Biological functions

  Renin is the rate-limiting enzyme that initiates the cascade generating the angiotensin peptides that regulate blood pressure, cell growth, apoptosis, and electrolyte balance. Renin is a hormone that ultimately integrates cardiovascular and renal function in the control of blood pressure as well as salt and volume homeostasis. Prorenin is activated by proteolytic enzymes such as trypsin and kallikrein. Acid treatment (optimal pH at 3.3) and low temperature fully or partially (~15%) activate prorenin. The binding of prorenin to the renin receptor changes the conformation of the prosegment to expose the active site to activate the enzyme.;

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