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1.
Mol Cell Endocrinol ; 332(1-2): 253-60, 2011 Jan 30.
Article in English | MEDLINE | ID: mdl-21075169

ABSTRACT

Cumulative evidence demonstrated effective downstream metabolism of pregnenolone in renal tissue. The aim of this study was to evaluate the expression and functional activity of cytochrome P450 side chain cleavage enzyme (CYP11A1), which converts cholesterol into pregnenolone, in adult rat kidney. Immunohistochemical labeling for CYP11A1 was observed in renal cortex and medulla, on structures identified as distal convoluted tubule and thick ascending limb of Henle's loop, respectively. Immunoblotting analysis corroborated the renal expression of the protein in inner mitochondrial membrane fractions. The incubation of isolated mitochondria with the membrane-permeant cholesterol analogue 22R-hydroxycholesterol resulted in efficient formation of pregnenolone, the immediate precursor for the synthesis of all the steroid hormones. The low progesterone production rate observed in these experiments suggested a poor activity of 3ß-hydroxysteroid dehydrogenase enzyme in renal mitochondria. The steroidogenic acute regulatory protein (StAR), involved in the mitochondrial import of cholesterol, was detected in renal tissue at both mRNA and protein level. Immunostaining for StAR showed similar distribution to that observed for CYP11A1. The expression of StAR and CYP11A1 was found to be higher in medulla than in cortex. This enhanced expression of steroidogenesis-related proteins correlated with a greater pregnenolone synthesis rate and higher steroid hormones tissular content measured in medulla. In conclusion, we have established the expression and localization of StAR and CYP11A1 protein, the ability of synthesizing pregnenolone and a region-specific content of sex hormones in the adult rat kidney. These data clearly show that the kidney is a steroid hormones synthesizing organ. It is proposed that the existence in the kidney of complete steroidogenic machinery would respond to a physiological significance.


Subject(s)
Cholesterol Side-Chain Cleavage Enzyme/metabolism , Kidney/enzymology , Animals , Carrier Proteins/metabolism , Cholesterol Side-Chain Cleavage Enzyme/genetics , Kidney/anatomy & histology , Male , Mitochondrial Membranes/enzymology , Phosphoproteins/genetics , Phosphoproteins/metabolism , Pregnenolone/biosynthesis , Progesterone/biosynthesis , Rats , Rats, Wistar , Receptors, GABA-A/metabolism , Testosterone/metabolism
2.
J Endocrinol ; 203(1): 155-65, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19648213

ABSTRACT

In the present study, we demonstrate the expression of heme oxygenase (HO) isozymes, HO-1 and HO-2 (listed as HMOX1 and HMOX2 in the MGI Database), in MA-10 Leydig tumor cells and its effect on steroidogenesis. The well-known HO inducer, hemin, increased both HO-1 and HO-2 protein levels and HO-specific activity. Induction of HO by hemin inhibited basal, hCG-, and dibutyryl cAMP (db-cAMP)-induced steroidogenesis in a reversible way. When we studied the effect of HO isozymes along the steroid synthesis, we found that steroidogenic acute regulatory protein levels were decreased, and the conversion of cholesterol to pregnenolone was inhibited by hemin treatment, with no changes in the content of cholesterol side-chain cleavage enzyme (P450scc). hCG and db-cAMP also stimulated the expression of HO-1 and HO-2, and HO enzymatic activity in MA-10 cells. Basal and hCG-stimulated testosterone synthesis was also inhibited by hemin in rat normal Leydig cells. Taken together, these results suggest that: i) at least one of HO products (presumably carbon monoxide) inhibits cholesterol transport to the inner mitochondrial membrane and Leydig cell steroidogenesis by binding to the heme group of the cytochrome P450 enzymes, in a similar way as we described for nitric oxide, and ii) hCG stimulation results in the induction of an antioxidant enzymatic system (HO) acting as a cytoprotective mechanism in Leydig cells, as already demonstrated in the adrenal gland.


Subject(s)
Heme Oxygenase (Decyclizing)/metabolism , Heme Oxygenase-1/metabolism , Leydig Cells/enzymology , Testosterone/biosynthesis , Animals , Carbon Monoxide/metabolism , Cell Line, Tumor , Chorionic Gonadotropin/metabolism , Dibutyryl Cyclic GMP , Isoenzymes/metabolism , Male , Phosphoproteins/metabolism , Rats , Rats, Sprague-Dawley
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