Renin is an aspartyl protease that raises blood pressure, retains sodium, and alters gene transcription to adversely affect the kidney and heart. Renin cleaves a decapeptide, angiotensin I, from a large hepatic protein, angiotensinogen. Angiotensin-converting enzyme activates angiotensin I to the octapeptide, angiotensin II, by removal of two amino acids from the carboxyl terminus. Angiotensin II interacts with AT1 receptors to mediate most renin effects. The system is involved with the pathology of the following: congestive heart failure, myocardial infarction, hypertension, and diabetes mellitus (renal damage). Inhibitors of the system are beneficial in treating these pathologies and include direct renin inhibitors, angiotensin-converting enzyme inhibitors, and angiotensin receptor antagonists.
The renin-angiotensin system is thought to be important in adaptations to low-salt diets and normal development of the kidneys in utero.
Control of Renin Release
Renin is secreted from the kidney in response to the following: lower renal artery blood pressure, reduced dietary sodium intake, sympathetic nerve activation, and prostaglandins. Renin release is inhibited by elevated renal artery pressure, increased sodium consumption, ß-receptor antagonists, and atrial natriuretic peptide.
Renin Tissue Localization and Molecular Biology
In addition to the kidney, renin (REN) mRNA is found in multiple organs, including the brain. The REN gene codes for a large 406 amino acid protein (pre-pro-renin). The removal of 23 amino acids from the carboxyl terminal results in the formation of prorenin. The final activation step removes 43 amino acids from the amino terminal to form the 340 amino acid active protein known as renin. Both renin and prorenin are secreted into the circulation. Prorenin can be activated by binding to its receptor even in the absence of conversion to renin. The enzyme converting prorenin to renin has not been identified but is believed to be specific to the kidney because nephrectomized patients or animals contain no renin in their circulation but prorenin is present. Inhibitors of the prorenin receptor have been shown to be beneficial in diabetic nephropathy and hypertension.
Behavioral Actions of Renin
Renin and other components of the renin-angiotensin system are present in the brain and are believed to impact memory negatively and to exacerbate Alzheimer’s disease and other neurodegenerative disorders, potentially because the prorenin receptor tends to promote the formation of reactive oxidative products. Prorenin receptors are present on substantia nigra neurons where they augment toxicity in dopaminergic neurons, potentially worsening Parkinson’s disease. Renin secretion polymorphisms also are one of five pathway-wide associations for schizophrenia. Results with the prorenin receptor and prorenin-processing enzyme are absolutely specific for the renin pathway and should assist in determining relevant behavioral effects of the system in the future. In contrast, angiotensin-converting enzyme inhibitors or polymorphisms have multiple behavioral effects, but these could be unrelated to the renin-angiotensin system because of the nonspecific nature of the angiotensin-converting enzyme. Alterations in angiotensin-converting enzyme activity have been associated with the following: greater physical activity, improved cognition, panic disorder, depression, suicide, autism, physical aggression, schizophrenia, and Alzheimer’s disease.