The enzyme 11-beta hydroxysteroid dehydrogenase type 2 plays a major role in blood pressure regulation. It metabolizes glucocorticoid hormones into derivatives with low affinity for the mineralocorticoid receptor, preventing its permanent occupancy by circulating cortisol, which is 100- to 1000-fold more abundant than aldosterone in the plasma. Inactivating mutations of the enzyme result in severe hypertension, as seen in children with apparent mineralocorticoid excess syndrome. In patients with essential hypertension, however, attempts to evidence enzyme deficiency have been inconclusive. In this pilot study, its catalytic activity was measured directly in aldosterone-sensitive sweat gland ducts collected from skin biopsy samples of 10 male normotensive subjects and 10 subjects with essential hypertension (more than 140 to 90 mm Hg) with no sign of hypermineralocorticism. Isolated ducts were assayed for nicotinamide-dinucleotide-dependent dehydrogenase activity (transformation of tritiated corticosterone into tritiated-11 dehydrocorticosterone, as measured by high-pressure liquid chromatography). Hypertensive patients exhibited significantly lower 11-beta hydroxysteroid dehydrogenase type 2 activity (9.7+/-4.7 femtomoles per 3 mm length of duct and per 10 minutes incubation, median+/-SD) than did normotensive subjects (15.9+/-2.6). Such defect was undetectable using the classical urinary corticosteroid metabolism indexes, probably because of compensatory mechanisms. Relations between these findings and blood pressure levels should benefit from direct enzyme measurements in the vasculature. In conclusion, this cross-sectional study points to partial 11-beta hydroxysteroid dehydrogenase type 2 deficiency as a novel feature of essential hypertension, which should stimulate search for new signaling pathways and therapeutical targets.

OBJECTIVES:Study the renal consequences of lithium therapy and find out whether lithium-induced chronic renal toxicity can provoke a progressive nephropathy, leading to advanced renal failure, requiring periodical dialysis.METHODS:Fifty-three patients treated with long-term lithium salts were included in the study. They had developed chronic renal failure (creatinine clearance inferior to 80 ml/min) not due to any other cause.RESULTS:These patients had received lithium salts for a mean period of 17.7 years. The mean reduction in creatinine clearance was of 2.23 ml/min/year. Final clearance correlated negatively with the duration of lithium administration. In 7 patients treated a mean of 22 years, progression towards terminal kidney failure required periodical dialysis. Around 30% of patients exhibited mild hypercalcemia.CONCLUSION:Lithium nephropathy inducing progressive renal failure is a reality. Its prevalence in patients treated long-term with lithium should be assessed.

We report a single case documenting substantial improvement in the course of human immunodeficiency virus (HIV)-associated, biopsy-proven nephropathy after introduction of highly active antiretroviral therapy. Our case report joins several others recording improvement or stabilization in the course of nephropathy following better control of HIV replication.

The results of MR angiography at 1.0 T with digital intraarterial angiography in the screening of patients with suspected renal hypertension were compared. In this first phase of the study, 10 volunteers underwent examination with both two-dimensional (2D) with traveling saturation time-of-flight (TOF) magnetic resonance angiography (MRA) with various parameters to develop a protocol for evaluation of the renal arteries. In the second phase, 36 patients with suspected renovascular hypertension underwent both 2D TOF MRA and intraarterial digital angiography to evaluate the clinical value of MRA. The degree of stenosis was graded with a two-point scale. In volunteers, using 2D acquisitions C/N ratios indicated the best flip angle as being 55 degrees (p = .02). MRA showed 100% (70/70) of all main arteries and 86% (6/7) of all accessory renal arteries seen on angiography. MRA had a sensitivity of 94% (15/16) and a specificity of 98% (60/61) for detection of stenoses of greater than 50% present in 14 patients. 2D-TOF MRA at 1.0 T shows promise in the noninvasive diagnosis of patients with suspected renovascular hypertension.

Enzymatic properties of the enzyme 11/3-hydroxysteroid dehydrogenase (11-HSD), which confers mineralocorticoid selectivity, have been explored in the aldosterone-sensitive collecting duct (CCD) and the aldosterone-insensitive Pars Recta (PR) of the rat kidney. After incubation of freshly isolated tubular segments with [3H]corticosterone (3H-B) or [3H]dehydrocorticosterone (3H-A), the rate of transformation of 3H-B into 3H-A (dehydrogenase activity), or the reverse reaction (reductase activity) were measured by HPLC. Vmax, for dehydrogenase activity was found to be 8− to 10-fold higher in CCD than PR. The enzyme functions over a very wide range (0.1–5000 nM) of corticosterone concentration. In CCD, enzyme kinetics suggest either the presence of two 11-HSD forms, differing by their affinity for corticosterone, or complex kinetics. Addition of NAD or NADP to permeabilized tubules revealed that dehydrogenase activity is NAD-dependent in CCD and NADP-dependent in PR. Cofactor addition was ineffective in intact tubules. CCD exhibited an exclusive dehydrogenase activity, whereas in PR dehydrogenase and reductase activity were found. No regulation of dehydrogenase activity could be evidenced in adrenalectomized rats receiving or not aldosterone, corticosterone or dexamethasone, for 2 h, 3 days or 4 days. We conclude that 11-HSD in the CCD and PR differs by its Vmax and cofactor dependence. Corticosteroid hormones do not influence 11-HSD activity.

To investigate the mechanisms involved in the in vivo aldosterone selectivity of the mineralocorticoid receptor (MR), we studied the respective contribution of the receptor and the enzyme 11 beta-hydroxysteroid dehydrogenase (11HSD), which converts glucocorticoids into inactive metabolites. Using a cotransfection assay in CV-1 cells, aldosterone activated mouse mammary tumor virus promoter through human MR (hMR) with an ED50 of 0.01 nM. An at least 100-fold higher concentration of cortisol (F), corticosterone (B), or dexamethasone was required to obtain half-maximum transactivation, indicating a functional preference of hMR for aldosterone over glucocorticoids. The catalytic activity of 11HSD was analyzed using HPLC by measuring the tritiated metabolites produced in CV-1 and COS cells. Both cell types displayed a significant dehydrogenase activity (20 fmol/10 min.10(3) cells) inhibitable by carbenoxolone, but no detectable reductase activity. In this model, B was more rapidly metabolized than F. Carbenoxolone treatment of hMR-transfected CV-1 cells did not result in a shift of the dose-response transactivation curves of B and F toward lower concentrations, ruling out the implication of 11HSD in the aldosterone MR selectivity of these conditions. Despite similar affinity constants of aldosterone and glucocorticoids for the hMR, kinetic experiments showed that the off-rate of aldosterone from hMR was 5 times lower than that of glucocorticoids, pointing to an intrinsic discriminating property of the receptor. Therefore, we propose that in addition to 11HSD, MR plays an active role in the mechanism of aldosterone selectivity.

The expression of mineralocorticoid receptors (MR) and 11 beta-hydroxysteroid dehydrogenase (11HSD) activity has been investigated in the epidermis and appendages of the human skin. Aldosterone binds to MR and regulates sodium transport in tight epithelia. Mineralocorticoid selectivity is achieved through coexpression of MR and 11HSD, which prevents permanent MR occupancy by glucocorticoids. Some forms of hypertension may involve abnormalities of MR and/or 11HSD. However, their direct assessment in humans remains difficult in the kidney or colon. This led us to explore this system in human skin easily accessible to biopsy. In situ hybridization with specific MR complementary ribonucleic acid probes and immunohistochemistry using three different anti-MR antibodies showed that MR was expressed at both the messenger ribonucleic acid and protein levels in the keratinocytes of the epidermis, in the sweat and sebaceous glands, and in the hair follicles. A significant 11HSD activity was found in isolated sweat gland ducts (5 fmol/3-mm length.10-min incubation with 10 nmol/L corticosterone as substrate) and was very low in the epidermis. In both structures, reductase activity was 10 times lower than that of dehydrogenase. Studies on the cofactor specificity of the enzyme showed a nicotinamide-adenine-dinucleotide preference in sweat glands, contrasting with a nicotinamide-adenine-dinucleotide phosphate dependence in epidermis. Human skin appears as a new target for aldosterone because it coexpresses MR and 11HSD. Our findings present the possibility to explore the functionality of the MR system in human tissue and its implications in various physiopathological situations.

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) plays a major role in the protection of the mineralocorticoid receptor (MR). This cellular mechanism of aldosterone selectivity relies on the coexpression of MR and 11 beta-OHSD in the same cells. Localization of renal 11 beta-OHSD along the nephron is reviewed; comparison of data contained in different species is made; and original data is presented to show that the catalytic activity of the enzyme in tubules from human kidney is the highest in the mineralocorticoid-sensitive distal nephron.

The mineralocorticoid receptor displays equal affinity for aldosterone and corticosterone. It has been proposed that aldosterone selectivity in vivo is achieved by the conversion of corticosterone into its inactive metabolite 11-dehydrocorticosterone by 11 beta-hydroxysteroid dehydrogenase (11 beta HSD). To test this hypothesis, we transfected rat liver 11 beta HSD cDNA into TBM cells, a sodium-transporting cell line. These cells respond equally well to aldosterone and corticosterone, indicating that endogenous 11 beta HSD is expressed at low levels in TBM cells. Although exogenous rat liver 11 beta HSD was expressed at high levels in transfected cells, mineralocorticoid selectivity was not observed. By contrast, the biologically inactive 11-dehydrocorticosterone was readily converted into corticosterone, a potent agonist for sodium transport. Our results indicate that rat liver 11 beta HSD behaves predominantly as a reductase in TBM cells. Another 11 beta HSD isoform is likely to be responsible for the dehydrogenase reaction in aldosterone-responsive cells.

(1993). Familial Mediterranean Fever-Associated Amyloidosis. Renal Failure: Vol. 15, No. 3, pp. 379-384.

Eleven-beta-hydroxysteroid dehydrogenase (11 beta OHSD) protects the aldosterone receptor (MR) against its occupancy by glucocorticoid hormones. We examined the intrarenal distribution of 11 beta OHSD, as compared to that of MR. MR were localized in histological sections from rabbit kidney, using immunohistochemical methods with an anti-MR monoclonal antibody. 11 beta OHSD activity was measured in isolated tubular segments from rabbit, rat and mouse kidneys. Tubules were incubated in the presence of tritiated corticosterone (3H-B:2 x 10(-8)M). Then the rate of degradation of 3H-B into 3H-11-dehydrocorticosterone (3H-A) was determined by HPLC. MR was immunodetected in the distal tubule and the collecting duct. No positive staining was present in the proximal tubule. The conversion rate of 3H-B into 3H-A was high (approximately 80%) in the distal and collecting tubule. It was low in the proximal tubule (less than 15%) except in the rat (approximately 50%). These results indicate that MR and 11OHSD are colocalized along the mammalian nephron. This colocalization constitutes a strong argument in favor of the MR-protective role of 11 beta OHSD, and of a role of a defect of this enzyme in the genesis of some types of arterial hypertension.

Sabine Kenouch, MD, Department of Nephrology, Hôpital Bichat, 46, rue Henri Huchard, F-75018 Paris (France) Sir, We read with interest the letter of Béné et al. [1]. Based upon the absence of 1⁄8A deposits in all but one autopsy specimens of kidney from 54 AIDS patients the authors express the opinion that the presence of IgA mesan-gial deposits in the 2 patients with AIDS-re-lated complex we reported in 1990 [2] was purely coincidental. In their opinion, these patients were suffering from IgA nephropathy (IgAN) not related to HIV infection. Though the occurrence of two unrelated diseases cannot be excluded, we would like to stress that since our paper was published we have observed 1 additional case of IgAN in a patient with overt AIDS. Five other cases have been published. 4 by Bargman et al. [3] and 1 by Jindal et al. [4]. In addition to the similarities of abnormalities of the IgA immune system found in HIVinfected patients and in those with IgAN [5, 6], Warmold et al. [7] found higher levels of binding to matrix components of normal human kidney of serum IgA both from patients with IgA nephropathy and AIDS than from normal controls. It must also be stressed that HIV-infected patients with IgAN were all Caucasian [Bargman, personal commun. for her patients], a finding in keeping with the rarity of primary IgAN in blacks. In this respect, one would like to know what was the ethnic origin of the patients of Béné et al. [1]. Referring to the absence of IgA mesangial deposits in the patients of Jackson et al. [6], one might assume that the majority of them were black since the authors are from Alabama. In conclusion, though a coincidence cannot be definitely excluded, we think that Caucasian HIV-infected patients are at a higher risk for mesangial IgA deposition. References Béné, M.-C; Canton, P.; Amid, C; May, T.; Faure, G.: Absence of mesangial IgA in AIDS: A postmortem study. Nephron 58: 240-241 (1991). Kenouch, S.; Delahousse, M.; Méry, J.Ph.; Nochy, D.: Mesangial IgA deposits in two patients with AIDS-related complex. Nephron 54: 338-340 (1990). Bargman, J.M.; Katz, A.; Miller, D.C.; Guo J.J.W.; Schoeneman, M.J.; Ghai, V.S.: IgA nephritis in HIV positive patients. A new AIDS nephropathy (abstract). J. Am. Soc. Nephrol. 7: 304 (1990). Jindal, K.K.; Trillo, A.; Bishop, G.; Hirsch, D.; Cohen, A.: Crescentic IgA nephropathy as a manifestation of human immune deficiency virus infection. Am. J. Nephrol. 77:147-150 (1991). Procaccia, S.; Lazzarin, A.; Colucci, A.; Gaspar-ini, A.; Forcellini, P.; Lanzanova, D.; Uberti Foppa, C; Novati, R.; Zanussi, C: IgM, IgG and IgA rheumatoid factors and circulating immune complexes in patients with AIDS and AIDS-related complex with

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) is thought to be a protective enzyme of the mineralocorticoid receptor (MR). We have previously demonstrated (Bonvalet et al, J Clin Invest 86:832-837, 1990) that 11 beta-OHSD is colocalized with MR along the rabbit nephron. In the present study, we examined whether 11 beta-OHSD is similarly located along the nephron of other mammals. Various tubular segments were microdissected from the mouse, rat, and rabbit nephron, and incubated for two hours at 37 degrees C in the presence of 11 nM [3H]-corticosterone (B). Thereafter, the respective amounts of B and [3H]-11dehydrocorticosterone (A) in the incubation solution were measured by HPLC. In the rabbit, the mouse and the rat, about 520 pmol/10 mm of B were transformed into A in tubular segments possessing MR, that is, the distal parts of the nephron (distal and collecting tubule). Differences appeared in the aldosterone-insensitive proximal tubule; in both the initial and final parts of this segment, 11 beta-OHSD activity was low (26 pmol/10 mm) in the rabbit and the mouse, and relatively high in the rat (328 pmol/10 mm). In the cortical part of the loop of Henle, where the presence of MR is still under discussion, 11 beta-OHSD activity was low in the mouse (70 pmol/10 mm), high in the rat (533 pmol/10 mm) and intermediate in the rabbit (227 pmol/10 mm). The comparison of these results with previous data obtained with immunohistochemical methods suggests that the proximal and distal nephron might express different isoforms of 11 beta-OHSD.