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EDITORIAL FOCUS
Institute of Pharmacology and Toxicology, Charité Hospital, Humboldt-University Berlin, D-10117 Berlin, Germany
TISSUE-SPECIFIC CHANGES in gene expression during maturation may provide important insights into tissue-specific gene expression patterns during pathogenesis. In this context, the cell- or tissue-surrounding environment or stroma has been recognized as an important regulator (11). The great diversity observed in the composition and morphology of the extracellular environment contributes significantly to a cell-/tissue-specific pattern of gene expression (3, 7). Multiple effects of the extracellular environment on cellular characteristics at different stages of maturation have been described (1). In addition, the environmental framework of cells and tissue is greatly modified during disease development, which may result in prominent variances of gene expression (9).
The article of Nishimura and colleagues (7a) in this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology demonstrates significant changes of angiotensin receptor expression in the kidney, adrenal gland, and vasculature during maturation in fowl. The studied angiotensin receptor (cAT1) is a homologue to the mammalian angiotensin type 1 receptor (AT1 receptor) with 75% amino acid identity. The tissue-specific maturation-dependent changes in cAT1 expression observed in this study are an excellent demonstration of the importance of studying gene expression by focusing on time and tissue specificity. These results are consistent with studies in mammalian species demonstrating a maturation-dependent expression of the AT1/AT2-receptor subtypes (4). Parallel to the time dependency of mammalian AT-receptor expression, several studies have shown that the changes in AT-receptor expression during maturation are also tissue specific (5, 10). But how does a distinct AT-receptor gene expression pattern in specific tissues during maturation impact on AT-receptor-mediated function, and, furthermore, what is the relevance of these processes for AT-receptor dysfunction and AT-receptor-associated pathological processes?
Nishimura and colleagues investigated the endothelium-dependent effects of ANG II on vasoregulation of abdominal aortae in fowl in an ex vivo assay. ANG II stimulation of abdominal aortae led to a potent vasodilation, which was eliminated after removal of the endothelium. However, the results of this AT-receptor-dependent function did not correlate with the cAT1-expression pattern in abdominal aortae. These data are in contrast to the vasoregulatory effects of ANG II in humans, where ANG II is a potent vasoconstrictor. Other groups have investigated atypical AT receptors in the central nervous systems of gerbils, a specific rodent type, and postulated their functional relevance during cerebral ischemia (6). It appears that, in addition to the present elegant study on tissue- and maturation-dependent expression patterns of AT receptors, future studies are required to translate these results into function-related gene expression profiles. Until these data are available, one has to be careful in extrapolating from changes of gene expression in non-mammalian species or specific rodents, such as the gerbil, to functional changes and to comparable processes in humans.
What might be the impact of the observed distinct expression pattern during maturation on AT-receptor dysfunction or AT-receptor-mediated pathologies? What is the relevance of these findings for human physiology or pathophysiology? It has been previously shown in many studies that the reconstitution of an embryonic gene profile might play a central role in the pathogenesis of multiple diseases (11). For example, the mammalian angiotensin type 2 receptor (AT2 receptor), which is normally expressed in embryonic phases and disappears during development, is strongly reexpressed after myocardial infarction and stroke (4). Furthermore, embryonic gene expression patterns are frequently observed in pathologically altered tissues, e.g., in the failing heart. Therefore, studies on the regulation of gene expression during maturation and the knowledge of the modifying mechanisms will heavily contribute to the understanding of pathogenic processes and their future treatment.
The study by Nishimura and colleagues also reflects the complexity of specific gene expression patterns in different tissues at different time points. The microenvironment of cells and tissue, including extracellular matrices, ions, cytokines, and growth factors, is a highly flexible framework also prominently regulated during maturation. In addition, this extracellular environment is markedly modified during pathological processes, e.g., during diabetes or obesity. For example, hyperglycemia or hyperinsulinemia are important regulators of AT-receptor expression and function in mammalian species, comparable to the modifications during maturation (8). Glucose-/insulin-mediated AT-receptor expression may have pivotal effects on AT-receptor-mediated cardiovascular functions associated with insulin resistance or diabetes. Simultaneously with the alteration of AT-receptor expression during disease progression, tissue-specific differences have been observed in diabetes. For instance, Brown and colleagues (2) demonstrated that AT-receptor density is markedly upregulated in the heart and liver of diabetic rodents, whereas there is a decrease in renal density.
In conclusion, maturation-dependent and pathogenesis-associated gene expression profiles might be closely related. Therefore, with an increasing number of studies demonstrating the specificity or selectivity of gene expression during maturation or pathogenesis, the knowledge of disease-/tissue-specific gene expression will improve. This is further supported by recently developed molecular techniques targeting gene expression in a time- and tissue-specific manner. On the basis of these data, therapeutic strategies with improved selectivity and specificity may be launched.
FOOTNOTES
Address for reprint requests and other correspondence: T. Unger, Institute of Pharmacology and Toxicology, Charité Hospital, Humboldt-Univ. Berlin, Dorotheenstr. 94, D-10117 Berlin, Germany (E-mail:
thomas.unger{at}charite.de).
REFERENCES
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 M. L Chappellaz and F. G Smith Dose-dependent systemic and renal haemodynamic effects of angiotensin II in conscious lambs: role of angiotensin AT1 and AT2 receptors Exp Physiol, November 1, 2005; 90(6): 837 - 845. [Abstract] [Full Text] [PDF]
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