Schlüsselwort: flutamide (MeSH)

Influence of testosterone on proteinuria and nephropathy in the rat models of chronic renal disease Albuminuria associated with chronic renal disease is the most important poly-genetic characteristic for the origin of cardiovascular as well as renal diseases. Many studies have revealed that androgens such as testosterone are of paramount importance for the progression of chronic renal disorders. For example, there is an enhanced de-cline of renal functions in male compared to female patients leading to an accelerat-ed formation of proteinuria as well as albuminuria. Due to their genetically determined mode animal models such as MWF as well as Dahl/SS-rats can be employed to show the correlation between albuminuria and their hormonal balance. The aim of this work was to verify whether it is possible to influence albuminuria in combination with different accompanying phenotypic characteristics such as blood pressure by castration. By this procedure testosterone should have been eliminated nearly com-pletely. The studies were performed in MWF and Dahl/SS-rats using Wistar rats as control group. Further the inhibition of all testosterone receptors in combination with castration and hormone replacement therapy was investigated. In preliminary studies to this work, three different aspects were covered. Firstly, physiological values of tes-tosterone in every rat strain were evaluated. Secondly, it could be shown that castra-tion of MWF as well as Dahl/SS-rats has independent from its timing a protective ef-fect towards the origin of an albuminuria. Already one week after castration a signifi-cant decline of an albuminuria could be detected even in rats with a progressed renal disorder. Thirdly, it was evaluated whether physiological values of testosterone could be achieved by its substitution to be able to perform the hormone replacement thera-py. On the basis of the preliminary studies a group design could be elaborated and used within this work. As a double controlled study a hormone substitution after cas-tration in parallel with the inhibition of testosterone receptors by flutamide - a selec-tive antagonist against androgens receptor - was performed. A clear and significant decline of an albuminuria could be shown within the castrated groups in both rat populations - namely MWF and Dahl/SS. Castration was performed at 10 weeks of age. The treatment with flutamide revealed that this decline was solely due to effect of testosterone. An effect on blood pressure in all examined study groups did not show a significant change concluding that testosterone does not have a detectable effect on blood pressure. Nevertheless, a direct correlation of presence and absence of testosterone and renal clearance of albumin could be impressively demonstrated within this work. After castration, the degree of albuminuria decreased about 50%. This effect could further be dramatically increased by additional inhibition of testos-terone receptors. In addition, different other phenotypic characteristics were evaluat-ed. The determination of a biomarker for renal function called cystatin C did not re-veal a significant difference between the different study populations. The histological-ly determined parameters showed a regression of renal impairment in castrated as well as testosterone and flutamide medicated study groups. Renal impairment mark-ers Kim1 and Ngal were determined molecular genetically. Results here also showed that values significantly decreased after castration and subsequent medication with testosterone as well as flutamide. The values obtained were comparable to values of the control Wistar group. Interestingly, Kim1 also showed decreasing values after pure castration. The obtained results of the performed study provide significant evi-dence that albuminuria in MWF as well as Dahl/SS-rats could be decreased after nearly complete elimination of testosterone production and inhibition of testosterone receptors. In addition, histological markers as well as molecular markers such as Ngal and Kim1 support these findings by testifying a decline in renal impairment. The results of this set the stage for potential translations of these findings into individual and standardized therapeutic strategies for treatment or prevention of renal diseases in humans.