Figure 1 Renin-Angiotensin-Aldosterone pathway (1)

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Figure 2 a) 3D structure of a renin molecule (17)    b) Schematic of the Renin molecule c) Angiotensinogen binding and cleavage by renin

Figure 3 The Prorenin molecule

 

 

 

 

 

 

 

Introduction

The renin-angiotensin system is one pathway that the body uses to elevate blood pressure. The focus of our research has been on the enzyme renin and its precursor prorenin. The newly discovered prorenin receptor is a promising new area of research. With the use of rat models, a better understanding of the role of prorenin in the body can be obtained and as well, uncover novel therapeutic methods for hypertension treatments.

The Renin-Angiotensin Sytem in Blood Pressure Elevation

Renin is an enzyme that functions to convert angiotensinogen, which is released from the liver, into angiotensin I. Another enzyme called Angiotensin Converting Enzyme (ACE) further converts angiotensin I into angiotensin II which acts on three systems to increase blood pressure: the hypothalamus inducing thirst and drinking, on the blood vessels to cause vasoconstriction and the adrenal cortex causing release of aldosterone which leads to salt and water retention in the body. (1)

Renin and Prorenin

The structure of the renin molecule consists of two homologous lobes with a cleft in between (2)The cleft serves as the active site for binding and converting angiotensinogen (2).

Renin is produced from a precursor molecule called prorenin from the kidneys. This precursor molecule is basically the renin enzyme but with an additional 43 amino acid N-terminal peptide called the prosegment. This additional peptide segment covers the active site of renin functioning to block  angiotensinogen from binding renin (2).

Originally, it was thought that there was only one way to activate renin which is cleavage of this N-terminal peptide exposing the active site for angiotensin binding and conversion. This method is known as proteolytic cleavage (2).

For many years, prorenin was thought to be an inactive precursor to renin serving no physiological role. High levels of prorenin circulating in the blood intrigued scientists, as it was found at concentrations 5 to 10 times higher than renin (3).

Recent studies have discovered the existence of a prorenin receptor (PRR) which may elucidate a more active role for prorenin. It is now known that a second method of renin activation exists termed non-proteolytic cleavage. The receptor is located at the surface of the cell and was found to be a 350 amino acid protein with a single transmembrane domain (4).

This prorenin receptor is capable of binding both prorenin and renin however, no internalization or degradation of either molecule occurs (2). When prorenin binds, the receptor induces a conformational change in the precursor molecule causing the 43 amino acid peptide to fold away from the active cleft and expose the active site (2,5). Angiotensinogen can then bind and be converted. This receptor provides a means for prorenin to gain enzymatic activity that is comparable to renin without cleavage of the prosegment. Renin can also bind to this receptor, however, there is a higher affinity for prorenin binding. This receptor has shown to enhance angiotensin I generation, increasing the catalytic activity of renin approximately four times that of soluble renin (6).

The prorenin receptor is mainly expressed in vascular smooth muscle cells (SMC) and renal mesangial cells (7). It was also found to be expressed in the heart, brain and placenta associated with smooth muscle cells (6). Knowing where this receptor is expressed will aid scientists in understanding the role for prorenin in hypertension.