Urodilatin-Renal Natriuretic Peptide?
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Urodilatin-Renal stimulates particulate guanylate cyclase in these cells, also with equal potency to ANP (12). Because Natriuretic Peptide? this new peptide possesses vasorelaxant properties when tested in an in vitro bioassay system ( 1 1 ), these authors termed it urodilatin, in parallel with the term In 1 98 1 , the report by DeBold et a!. (1) of potent cardiodilatin that they had earlier suggested for the natriuretic activity in extracts of cardiac atria ush- name of the precursor peptide (13). ered In the era of atrial natriuretic peptide (ANP). In Little is known at this juncture of the site of syn- just a few short years, the amino acid sequences of thesis and secretion and the mechanism of action of ANP and its prohormone were determined and its this newest member of the natriuretic peptide family. gene structure was elucidated, and the tissues in The absence of detectable urodilatin in the circula- which it was synthesized were Identified (for review. tion (1 4) argues for a kidney-specific site of synthesis. see references 2 and 3). At the same time, the biolog- Immunohlstochemical studies and radioimmuno- ical actions of ANP were being recognized as poten- assay of renal extracts demonstrate a-ANP immu- tially key to the integration of cardiovascular and noreactivity in renal tissue, interpreted to show renal function and the control of body fluid volumes; either de novo synthesis of the peptide or internali- receptors were identified and characterized in target zation of circulating a-ANP by the kidneys (15,16). tissues, and the cellular actions of the peptide were Because the addition of four amino acids to the 28- related to activation of a membrane-bound guanylate amino-acid a-ANP taken up by renal cells from the cyclase with production of cGMP (2,3). Thus, a com- circulation would be a truly novel form of peptide plete description of the biology of this peptide hor- metabolism, the presumption is that urodilatin re- monal system. from gene structure and transcrip- suits from a processing pathway of the ANP gene tion, through translation, processing, and secretion, product that is unique to the kidneys. Antisera to a- to receptor binding, activation of cellular signalling ANP show a great deal of cross-reactivity with uro- mechanisms, and final action in target tissues be- dilatin (1 7), and these earlier studies could well have came available in a dazzingly short time, reflecting detected the latter peptide rather than a-ANP; im- the power and pace of contemporary scientific re- munohistochemical studies with an antiserum rec- search. ognizing the N-terminal region of urodilatin (with no Yet, despite this explosion of information, there cross-reactivity to a-ANP) localize the immunoreac- has arrived no clear consensus of the role of ANP in tivity to the same segments as shown when anti-a- volume homeostasis. Despite several experimental ANP antiserum is used ( 1 3). Moreover, chromato- settings suggesting a role for ANP in the body fluid graphic analysis of renal extracts containing pep- economy (2-4), telling physiological studies in intact tides of low molecular weight indicates that most animals suggest that interruption of the circulating ANP-like activity elutes with urodilatin rather than ANP system results in no discernible alteration in with a-ANP itself (1 3, 1 8). Thus, evidence for a renal fluid regulation, save for an Impairment in the natrl- origin of urodilatin is strong, despite the failure to uretic response to an acute volume challenge (5.6). date to document expression of the ANP or urodilatin Thus, It is possible that the functions of ANP may gene in kidney tissue (17). relate as much to tissue-specific expression and ac- Studies examining the physiological effects of uro- tion as to circulating peptide levels, much as current dilatin indicate with uniformity that it mimics the research is suggesting to be the case for the renin- actions of a-ANP with respect to vasodilation, di- angiotensin system (7). The search for tissue ANP uresis and natriuresis, urinary cGMP excretion, and expression led to the discovery of brain natriuretic hemoconcentratIon (10,17). These studies for the peptide, a peptide that has significant amino acid most part have involved bolus intravenous injections homology to ANP but that is the product of a separate or Infusions of the peptide and may therefore not be gene (8). Brain natriuretic peptide is thought to func- relevant to an understanding of its true physiological tion chiefly in the nervous system as a transmitter role, because circulating urodilatin has not yet been but is also expressed in the heart (9) and has renal demonstrated. There is evidence to indicate that uro- actions mimicking ANP (8,10). dilatin is natriuretic in a lower dose than is a-ANP This quest received a new stimulus with the report (17.19,20). suggesting that its physiological actions in 1988 by Schulz-Knappe and associates of the iso- may be primarily referable to the kidneys. However, lation from human urine of a peptide structurally this conclusion is derived from studies comparing the identical to human a-ANP but with an amino-termi- effects of Intravenous or Intrarenal infusions of the nal extension of four amino acids (Figure 1) (11). ThIs peptldes. Both peptides are filtered at the glomerulus, 32-amino-acid peptide Is identical with amino acids but a-ANP undergoes extensive degradation by a neu- 95 through 126 of the precursor prohormone; it ex- tral metalloendopeptidase (EC 3.4.24.11) whereas hibits high-affinity binding to membranes from bo- urodilatin is resistant to such renal cortical peptidase vine adrenal medulla that matches that of ANP and activity (21). Consequently, a larger amount of fil- Journal of the American Society of Nephrology 1057 Editorial most closely linked to the effects of these peptides on sodium excretion. Although such a possibility opens up an exciting new area of research in the physiological and patho- physiological regulation of salt balance, it should be recognized that data supporting such a role of urodi- latin are based so far on circumstantial rather than direct evidence. Correlation of two biological events suggests but does not prove a causal relationship between them. Moreover, both sodium excretion and urodilatin excretion contain a term for urinary flow rate. If urodilatin concentration in urine was to be CO#{149}N determined in some way as a passive consequence of flow rate, the correlation in excretion could simply reflect such an effect of flow rate itself. Although Goetz, Drummer, and their co-workers present ar- guments making such an interpretation less likely Human ANP Human Urodilatin (1 4.22), studies designed specifically to address this issue are nevertheless needed to understand better Figure 1 . Amino acid structure of human a-ANP (left) and the meaning of variations in urodilatin excretion. urodilatin (right). A more fundamental reservation to the acceptance of a role of urodilatin in the regulation of sodium excretion relates to our ignorance regarding the peptides. Both peptides are filtered at the glomerulus, mechanisms by which its secretion is regulated and but a-ANP undergoes extensive degradation by a neu- its actions mediated. If urodilatin does Indeed func- tral metalloendopeptidase (EC 3.4.24. 1 1) whereas tion as a participant in the regulation of salt balance, urodllatin is resistant to such renal cortical peptidase Its secretion must in some way be linked to some activity (21). Consequently. a larger amount of fil- derivative of salt balance, most likely extracellular tered urodilatin could escape inactivation in proximal fluid volume. We currently recognize sympathetic segments to exerts its natriuretic effect by reaching efferent nerves and hormonal factors such as ANP more distal, sensitive sites, probably in the inner itself, anglotensin II, vasopressin. and possibly oth- medullary collecting duct (1 0). ThIs would result in ers to be the effector pathways adjusting the rate of greater potency because of resistance to degradation sodium excretion In response to changes in extracel- but would not necessarily reflect a greater sensitivity lular fluid volume. If urodilatin is the final step in at the cellular level. Because urinary urodilatin can- the pathway. then one or more of these, or other as not derive from peptide undergoing filtration from yet unrecognized, signals must trigger its secretion. plasma, the importance of this resistance to pepti- Is it secreted into the tubule lumen, as suggested by dase degradation in contributing to the biological Feller and associates (1 3), or Into the blood to reach actions of urodilatin must be examined in future receptor sites, as is apparently the case for clrculat- studies. ing ANP (3)? Answers to questions such as these Another approach to the question of the physiolog- should allow us to develop quickly a clearer picture ical role of urodilatin has been taken by Goetz and of the physiological role of urodilatin. colleagues (22) and Drummer and associates else- Although the nature of this picture is of course not where In this issue of JASN (14). They have been yet known, it is enticing to speculate that this peptide able to demonstrate in both dog and man that urinary may prove to have a major role in the intrarenal urodilatin excretion correlates closely with diurnal regulation of sodium excretion and may thereby help variations In sodium excretion and with the natri- to resolve the ambiguity regarding the functions of uresis after intravenous infusion of normal saline. a-ANP. Infusions of a-ANP produce profound effects In both species, these correlations were much on the systemic and renal circulations, the latter stronger than the relatively weak correlations ob- reflected by an Increase in glomerular filtration rate. served between sodium excretion and the concentra- and the argument has been advanced that the natri- tion of a-ANP measured in plasma.