RAS and sex differences in diabetic nephropathy

The androgen receptor (AR) signaling axis plays a critical role in the development, function and homeostasis of the prostate. The classical action of AR is to regulate gene transcriptional processes via AR nuclear translocation, binding to androgen response elements on target genes and recruitment of, or crosstalk with, transcription factors. Prostate cancer initiation and progression is also uniquely dependent on AR. Androgen deprivation therapy remains the standard of care for treatment of advanced prostate cancer. Despite an initial favorable response, almost all patients invariably progress to a more aggressive, castrate-resistant phenotype. Considerable evidence now supports the concept that development of castrate-resistant prostate cancer (CRPC) is causally related to continued transactivation of AR. Understanding the critical events and complexities of AR signaling in the progression to CRPC is essential in developing successful future therapies. This review provides a synopsis of AR structure and signaling in prostate cancer progression, with a special focus on recent findings on the role of AR in CRPC. Clinical implications of these findings and potential directions for future research are also outlined.

In men, hypoandrogenism is associated with features of the metabolic syndrome, but the role of sex hormones in the pathogenesis of the metabolic syndrome and diabetes is not well understood. We assessed the association of low levels of testosterone and sex hormone-binding globulin (SHBG) with the development of the metabolic syndrome and diabetes in men. Concentrations of SHBG and total and calculated free testosterone and factors related to insulin resistance were determined at baseline in 702 middle-aged Finnish men participating in a population-based cohort study. These men had neither diabetes nor the metabolic syndrome. After 11 years of follow-up, 147 men had developed the metabolic syndrome (National Cholesterol Education Program criteria) and 57 men diabetes. Men with total testosterone, calculated free testosterone, and SHBG levels in the lower fourth had a severalfold increased risk of developing the metabolic syndrome (odds ratio [OR] 2.3, 95% CI 1.5-3.4; 1.7, 1.2-2.5; and 2.8, 1.9-4.1, respectively) and diabetes (2.3, 1.3-4.1; 1.7, 0.9-3.0; and 4.3, 2.4-7.7, respectively) after adjustment for age. Adjustment for potential confounders such as cardiovascular disease, smoking, alcohol intake, and socioeconomic status did not alter the associations. Factors related to insulin resistance attenuated the associations, but they remained significant, except for free testosterone. Low total testosterone and SHBG levels independently predict development of the metabolic syndrome and diabetes in middle-aged men. Thus, hypoandrogenism is an early marker for disturbances in insulin and glucose metabolism that may progress to the metabolic syndrome or frank diabetes and may contribute to their pathogenesis.

Angiotensin-converting enzyme 2 (ACE2) is a homolog of ACE that counterbalances the actions of angiotensin (AT)II and promotes vasodilatation. Circulating ACE2 activity is increased in diabetes in experimental models. The role of ACE2 in human pathophysiology is unknown. We examined whether ACE2 activity is altered in patients with type 1 diabetes (T1D), with and without diabetic nephropathy. Quantitative ACE2 activity in serum was measured by a fluorometric assay in 859 patients with T1D in the Finnish Diabetic Nephropathy (FinnDiane) study and in 204 healthy controls. Pulse-wave analysis with augmentation index (AIx) measurement was performed in 319 patients with T1D and 114 controls. ACE2 activity was increased in men with T1D and microalbuminuria (30.2 ± 1.5 ngE/ml) when compared to patients without albuminuria (27.0 ± 0.5 ngE/ml, P < 0.05) or controls (25.6 ± 0.8 ngE/ml, P < 0.05). ACE2 activity was increased in male and female patients who were on ACE inhibitor (ACEi) treatment, also independently of albuminuria. Male and female patients with coronary heart disease (CHD) had significantly increased ACE2 activity (35.5 ± 2.5 vs. 27.0 ± 0.5 ngE/ml, P < 0.001 among male T1D patients vs. male controls). ACE2 activity correlated positively with systolic blood pressure (rs = 0.175, P < 0.001), AIx (rs = 0.191, P = 0.010) and diabetes duration (rs = 0.198, P < 0.001), and negatively with estimated glomerular filtration rate (rs = -0.109, P = 0.016) among male T1D patients. ACE2 activity increases with increasing vascular tone and when the patient with T1D has microvascular or macrovascular disease, indicating that ACE2 may participate as a compensatory mechanism in the regulation of vascular and renal function in patients with T1D.