ACE2- Ang 1-7-MAS Axis in Human Diabetic Nephropathy

Abstract

The angiotensin-converting enzyme 2 (ACE2)- angiotensin-(1-7) [Ang (1-7)]-MAS receptor (MAS) axis might act as a counter-regulatory system against the angiotensin-converting enzyme (ACE)- angiotensin II (Ang II)-AT1 receptor (AT1) axis. We studied renal ACE/ACE2-Ang 1-7-MAS expression in human diabetic nephropathy. The subjects were 17 diabetic nephropathy (DN) patients, 17 healthy kidney donors, and 11 minimal change nephrotic syndrome (MCNS) patients as disease controls. Double immunofluorescent staining of kidney sections for ACE and ACE2, Ang 1-7 and ACE2, or MAS and ACE2 was performed, and the results were observed by confocal microscopy. For MAS, immunostaining, in situ hybridization, and RT-PCR were also performed. The percentage area that was positively immunostained for MAS and the intensity of the staining were evaluated by computerized imaging analysis. The median serum creatinine values of the DN patients, MCNS patients, and controls were 1.1 mg/dl, 0.8 mg/dl, and 0.8 mg/dl, respectively, and the median proteinuria values of the DN and MCNS patients were 3.7 g/day and 6.8 g/day, respectively. ACE2 was mainly detected in the proximal tubules, but was also found in the glomeruli in all subjects. ACE2 co-localized with ACE, Ang 1-7, and MAS in the proximal tubules. Compared with the other specimens, the diabetic patients’ proximal tubules displayed increased ACE and decreased ACE2 expression. Tubular Ang 1-7expression was downregulated in the DN patients compared with the controls and MCNS patients. Tubular MAS expression (density/pixel) was significantly (P<0.001) downregulated in the DN patients [7.33 (6.26-9.68)] compared with the controls [24.51 (18.06-34.56)] and MCNS patients [23.75 (20.11-25.52)]. Conclusions: The tubular ACE2-Ang 1-7-MAS axis is downregulated in human diabetic nephropathy patients compared with healthy controls and MCNS patients