Angiotensin-converting enzyme (ACE) 2, a newly emerging component of the renin-angiotensin system, is presumed to be a counterregulator against ACE in generating and degrading angiotensin II. It remains to be elucidated how mRNA levels of these two genes are quantitatively regulated in the kidney and also what kind of clinicopathological characteristics could influence the gene expressions in humans. Seventy-eight cases of biopsy-proven renal conditions were examined in detail. Total RNA from a small part of each renal cortical biopsy specimen was reverse transcribed, and the resultant cDNA was amplified for ACE, ACE2, and glyceraldehyde-3-phosphate dehydrogenase with a real-time PCR system. Then we investigated the relationship between clinicopathological variables and mRNA levels adjusted for glyceraldehyde-3-phosphate dehydrogenase. Statistically significant correlation was not observed between any clinicopathological variables and either of the gene expressions by pairwise comparison. However, a strong correlation was observed between the gene expressions of ACE and those of ACE2. Moreover, the ACE to ACE2 ratio was significantly higher in subjects with hypertension (HT) than that in subjects without HT. Whereas parameters of renal function, e.g. urinary protein excretion (UPE) and creatinine clearance (Ccr), are not significantly related to the ACE to ACE2 ratio as a whole, the HT status may reflect disease-induced deterioration of renal function. That is, UPE and Ccr of subjects with HT are significantly different from those without HT, in which a significant correlation is also observed between UPE and Ccr. Finally, stepwise regression analysis further revealed that only the HT status is an independent confounding determinant of the ACE to ACE2 ratio among the variables tested. Our data suggest that ACE2 might play an important role in maintaining a balanced status of local renin-angiotensin system synergistically with ACE by counterregulatory effects confounded by the presence of hypertension. Thus, ACE2 may exert pivotal effects on cardiovascular and renal conditions.

OBJECTIVE -Recent studies have proved that blockade of the renin-angiotensin system (RAS) retards the progression of diabetic nephropathy, whereas hyporeninemia is known as a typical state in diabetic subjects. The purpose of this study is to determine whether expression levels of RAS differ between nondiabetic and diabetic renal tissues with accurate quantitative method.RESEARCH DESIGN AND METHODS -Subjects were 66 nondiabetic and 8 diabetic patients with biopsy-proven renal diseases. The eight diabetic subjects suffered from type 2 diabetes with overt proteinuria. Renal histology revealed typical diffuse or nodular lesions with linear IgG deposit on immunofluorescent staining and thickened basement membrane on electronic microscopy. Total RNA from a small part of the renal cortical biopsy specimens was reverse-transcribed, and the resultant cDNA was amplified for new major components of RAS (i.e., renin, renin receptor, angiotensinogen, ACE, ACE2, angiotensin II type 1 receptor, and angiotensin II type 2 receptor) and measured.RESULTS -Among these components, a significant upregulation was observed in the ACE gene in diabetic renal tissue.CONCLUSIONS -The results suggest that renal tissue RAS might be activated in the respect that ACE gene expression is upregulated in spite of a tendency to low renin expression in type 2 diabetic nephropathy. Diabetes Care 29:848 -852, 2006R ecently proposed mechanisms for the development of diabetic nephropathy include glomerular hyperfiltration (1), disorientation of intracellular signal transduction (2), and involvement of advanced glycation end products (3). Activation of the reninangiotensin system (RAS) by high glucose, mechanical stress, and proteinuria has been implicated in the major changes associated with diabetic nephropathy (4). Thus, renal tissue activation of RAS is thought to contribute to deterioration in renal function of diabetic nephropathy. Recently, a number of large-scale prospective studies have proven that blockade of the system with ACE inhibitors and angiotensin II receptor blockers (ARBs) retards the progression of diabetic nephropathy (5-11). Actually, several studies suggest that the RAS is activated especially at the early stage (12,13). However, from early studies, hyporeninemia has been well known as a typical state of circulatory RAS in diabetic subjects at the late stage (14,15). Although the tissue RAS is thought to be controlled independently of the circulatory RAS, this apparent paradox is still difficult to interpret. It is supposed that the tissue RAS is activated in contrast to the circulatory RAS, and several non-or semiquantitative evaluations were made. However, direct or quantitative evidence in human diabetic nephropathy is very scarce so far. Furthermore, new major components for RAS, renin receptor (RER) (16), and ACE2 (17) have emerged recently.The purpose of this study is to determine whether expression levels of RAS including RER and ACE2 differ between nondiabetic and diabetic human renal tissues with full quantitative evalua...

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