Renin Substrates

Definition
The enzyme renin, which is found in extracts of kidney cortex, acts upon a protein substrate contained in the alpha-2 globulin fraction of the plasma to produce the decapeptide hypertensin I. This peptide is further degraded by a plasma enzyme to the powerfully vasoconstrictor octapeptide hypertension II which appears to be the effector substance of the renin-hypertensin pressor system 1.

Related Peptides
Renin substrate protein is a member of the serpin family.

Discovery
The history of the discovery of the renin-angiotensin system began in 1898 with the studies made by Tigerstedt and Bergman, who reported the pressor effect of renal extracts; they named the renal substance renin based on its origin. In 1934, Harry Goldblatt induced experimental hypertension in dogs by clamping a renal artery. About 1936, simultaneously in the Medical School of the University of Buenos Aires, Argentina, and in the Eli-Lilly Laboratories in Indianapolis, 2 independent groups of researchers, using the Goldblatt technique to produce experimental hypertension, demonstrated renal secretion of a pressor agent similar to renin. In the following years, both teams described the presence of a new compound in the renal vein blood of ischemic kidneys. This The final conclusion was that renin acted enzymatically on a plasma protein called the renin substrate to produce the new substance. In Buenos Aires, it was called hypertensin; in the United States, angiotonin. In 1958, Eduardo Braun Menéndez from Argentina and Irving H. Page from the United States agreed to name it angiotensin 2.

Structural Characteristics
The present understanding of the mechanism of the renin-hypertensin pressor system may be summarized in the following equations:

asp-arg-val-tyr-ileu-hls-pro-phe-his-leu-leu-val-tyr-ser – R (protein substrate)

I renin

asp-arg-val-tyr-ileu-Ms-pro-phe-his-leu + leu-val-tyr-ser - R

(hypertensin I) I Converting enzyme (CI-)

asp-arg-val-tyr-ileu-his-pro-phe + his-leu

(hypertensin II) vasoconstrictor

Renin breaks the leucyl-leucine bond of the substrate setting free hypertensin I it is clear that the point of attachment of the polypeptide substrate molecule to the parent protein must be at either the serine carboxyl or hydroxyl group. The renin substrate molecule is completely unaffected by a hypertensin-converting enzyme with which it is in intimate contact in the plasma. Neither is the purified polypeptide substrate affected by this enzyme. The leucine carboxyl group of hypertensin I becomes available only after this decapeptide is released from the substrate molecule. It is suggested therefore that this group must be free in order to satisfy the specific requirements of the converting enzyme and allow hydrolysis of the phenylalanyl-histidine bond of hypertensin I 1.

On the basis of the minimal octapeptide sequence of the renin substrate, a series of peptides was synthesized containing (3S, 4S)-4-amino-3-hydroxy-6-methylheptanoic acid (statine) or (3S,4S)-4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA) at the P1P1' position. Some of these peptides also contained Nin-formyltryptophan at the P5, P3, or P3' position. Renin-inhibitory potency varied over a wide range (from inactive to IC50 = 3 nM). Potency was reduced by at least 10-fold when the peptide was shortened by two residues at either the amino or carboxy terminus. Studies on the plasma renins of four nonhuman species suggest that the isoleucine-histidine segment at the P2'P3' position is important to defining the human specificity of the substrate 3.

A synthetic tetradecapeptide, H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Ser-OH, which corresponds to the 13 amino terminal residues of human angiotensinogen plus a carboxy terminal serine to replace a suggested site of carbohydrate attachment, has been shown to be a good substrate for human kidney renin . Thus, this synthetic renin substrate should permit more specific measurement of human kidney renin activity 4.

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Mode of Action
The enzyme renin, which is found in extracts of kidney cortex, acts upon a protein substrate contained in the alpha-2 globulin fraction of the plasma to produce the decapeptide hypertensin I. This peptide is further degraded by a plasma enzyme (2) to the powerfully vasoconstrictor octapeptide hypertension II which appears to be the effector substance of the renin-hypertensin pressor system 1.

Functions
Synthetic renin substrates are useful as renin inhibitors and in specific measurement of human kidney renin activity 3, 4.

References
1.Skeggs LT Jr, Kahn JR, Lentz K, Shumway NP (1957). The preparation, purification and amino acid sequence of a polypeptide renin substrate. J Exp Med., 106:439-453.
2.Basso N, Terragno NA (2001). History About the Discovery of the Renin-Angiotensin System. Hypertension. 38(6):1246-1249.
3.Hui KY, Carlson WD, Bernatowicz MS, and Haber E (1987). Analysis of structure-activity relationships in renin substrate analogue inhibitory peptides. J med chem., 30(8):1287-1295.
4.Poe M, Wu JK, Lin TY, Hoogsteen K, Bull HG, Slater EE (1984). Renin cleavage of a human kidney renin substrate analogous to human angiotensinogen, H-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu-Val-Ile-His-Ser-OH, that is human renin specific and is resistant to cathepsin D. Anal Biochem., 140(2):459-467.

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