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Background: Angiotensin-converting enzyme (ACE) 2 (ACE2) is expressed mainly in the heart and kidney and forms angiotensin-1-7 from angiotensin II. ACE2 might act in a counterregulatory manner to ACE. There is little information about renal ACE and ACE2 expression in human diabetic nephropathy., Study Design: Cross-sectional study., Setting & Participants: Kidney tissue from 20 patients with type 2 diabetes and overt nephropathy and 20 healthy kidney donors., Predictor: Diabetes status., Outcomes & Measurements: Renal expression of ACE and ACE2 assessed by means of immunohistochemistry and in situ hybridization. Correlation between ACE and ACE2 expression and levels of various biochemical parameters., Results: Decreased ACE2 and increased ACE expression in both the tubulointerstitium and glomeruli resulted in a significant (P < 0.001) increase in ACE/ACE2 ratio in patients with diabetes with overt nephropathy compared with controls, although ACE messenger RNA in the tubulointerstitium did not significantly increase. ACE/ACE2 ratio correlated positively with values for mean blood pressure, fasting blood glucose, serum creatinine, proteinuria, and hemoglobin A(1c) and inversely with estimated glomerular filtration rate (P < 0.001)., Limitations: Inclusion of small number of human renal biopsy specimens with structural distortion of cortical tissue., Conclusions: The high ACE/ACE2 ratio in kidneys of patients with type 2 diabetes with overt nephropathy may contribute to renal injury.

Activation of a transcription factor, nuclear factor-kappaB (NF-kappaB), is a key step in the pathogenesis of diabetic nephropathy. In this study, we investigated the role of P-selectin, a platelet-derived adhesion molecule, in diabetic nephropathy by examining the activation status of NF-kappaB in the renal cortex of streptozotocin (STZ)-treated rats. The STZ treatment induced pathogenetic parameters such as increased creatinine clearance, increased blood glucose and massive albuminuria in a time-dependent manner. Electrophoretic mobility shift assays (EMSAs) with a specific probe, representing the P-selectin gene promoter, revealed the activation status of NF-kappaB in the STZ-treated rats, as judged by the time-dependent increase in the formation of the specific protein-DNA complexes. This increase was associated with the increased pathogenetic parameters. Supershift assays with specific antibodies revealed that p50, but not p52, p65, Rel B, or c-Rel, may be involved in the activation of NF-kappaB, though the component primarily responsible for the increase could not be determined. Western blot analysis confirmed an increase in P-selectin in STZ-treated rats. Notably, treatment with ammonium pyrrolidinedithiocarbamate, an antioxidant and inhibitor of NF-kappaB, inhibited the activation of NF-kappaB in STZ-treated rats and decreased P-selectin in the renal cortical tissue. Our results indicate that expression of the P-selectin gene is induced through the activation of NF-kappaB and that P-selectin may be involved in the pathogenesis of diabetic nephropathy.

ABSTRACT: Aim: Angiotensin-converting enzyme 2 (ACE2) is a type I membrane protein that antagonizes the action of angiotensin II. Because of the need for invasive kidney biopsy, little is known about the role of renal ACE2 in human kidney diseases. The authors studied if urinary ACE2 could provide a novel clue to renal ACE2 in chronic kidney disease (CKD). Methods: Subjects were 190 patients with CKD including 38 patients with diabetic nephropathy and 36 healthy subjects. Parameters were urinary ACE2 by enzyme-linked immunosorbent assay, blood pressure, casual plasma glucose, proteinuria, microalbuminuria, serum creatinine and estimated glomerular filtration rate. Urine and serum samples were also subjected to western blotting of ACE2. Results: Western blotting confirmed increased urinary ACE2 levels in patients with CKD. Urinary ACE2 was significantly higher in patients with CKD than healthy subjects (median 9.64 (interquartile range, 4.41-16.89) vs 1.50 (0.40-2.33) mg/g·creatinine, P < 0.001) and in patients with diabetic nephropathy than patients without diabetic nephropathy (median 13.16 (interquartile range 6.81-18.70) vs 8.90 (4.19-16.67) mg/g·creatinine, P < 0.05). No significant difference in urinary ACE2 was observed by the use of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker. Conclusion: Urinary ACE2 could be used as a non-invasive marker to understand the role of renal ACE2 in CKD. [ABSTRACT FROM AUTHOR]

Background: Angiotensin-converting enzyme (ACE)2 forms angiotensin-1-7 which may protect kidney in a counterregulatory manner to angiotensin II. Recent studies revealed increased ACE and decreased ACE2 expression in kidneys of patients with diabetic nephropathy. However, these changes may not be specific for diabetic nephropathy. We studied ACE and ACE2 expression in patients with IgA nephropathy. Methods: Renal ACE and ACE2 expression was assessed by immunohistochemistry and in situ hybridization in 30 patients with IgA nephropathy and 21 healthy controls. Correlation between ACE and ACE2 expression and levels of various biochemical parameters was also assessed. Gene expression was also assessed in minimal change nephrotic syndrome (MCNS) and membranous nephropathy (MN) as disease controls. Results: Reduced ACE2 expression (p < 0.01) and increased ACE expression in glomeruli (p < 0.001), and reduced ACE2 expression in tubulointerstitium (p < 0.001) were observed in patients with IgA nephropathy compared to healthy controls, although the changes in ACE2 mRNA were not statistically significant. Reduced renal ACE2 expression was also found in MN but not in MCNS. Correlation between renal ACE and ACE2 expression and proteinuria was not observed in IgA nephropathy. Conclusion: IgA nephropathy is associated with increased ACE and decreased ACE2 expression in kidneys, as in diabetic nephropathy. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]