A polycystin-2 protein with modified channel properties leads to an increased diameter of renal tubules and to renal cysts.

Mutations in the PKD2 gene cause autosomal-dominant polycystic kidney disease but the physiological role of polycystin-2, the protein product of PKD2, remains elusive. Polycystin-2 belongs to the transient receptor potential (TRP) family of non-selective cation channels. To test the hypothesis that altered ion channel properties of polycystin-2 compromise its putative role in a control circuit controlling lumen formation of renal tubular structures, we generated a mouse model in which we exchanged the pore loop of polycystin-2 with that of the closely related cation channel polycystin-2L1 (encoded by PKD2L1), thereby creating the protein polycystin-2poreL1. Functional characterization of this mutant channel in Xenopus laevis oocytes demonstrated that its electrophysiological properties differed from those of polycystin-2 and instead resembled the properties of polycystin-2L1, in particular regarding its permeability for Ca2+ ions. Homology modeling of the ion translocation pathway of polycystin-2poreL1 argues for a wider pore in polycystin-2poreL1 than in polycystin-2. In Pkd2poreL1 knock-in mice in which the endogenous polycystin-2 protein was replaced by polycystin-2poreL1 the diameter of collecting ducts was increased and collecting duct cysts developed in a strain-dependent fashion.

Long-term sensitivity of uterus and hypothalamus/pituitary axis to 17beta-estradiol is higher than that of bone in rats.

UNLABELLED: We examined the long-term sensitivity of uterus and bone to low-dose 17beta-estradiol in a 4-month experiment in OVX rats and found that a dose of estradiol that fully protected against uterine atrophy did not protect against bone loss. Our results suggest higher estrogen sensitivity of the uterus compared with bone. INTRODUCTION: Estrogen is essential for the function of reproductive tissues and for the normal acquisition and maintenance of bone mass in females. This study was designed to examine the long-term sensitivity of the uterus and bone to low-dose estrogen. MATERIALS AND METHODS: In preliminary experiments, we determined the lowest subcutaneous dose of 17beta-estradiol able to fully protect against uterine atrophy in ovariectomized (OVX) rats. This dose was found to be 1.5 microg/kg, given five times per week. Subsequently, groups of sham-operated (SHAM) or OVX 6-month-old rats (n = 8 each) were subcutaneously injected with vehicle or 1.5 microg/kg 17beta-estradiol five times per week. All animals were killed 4 months after surgery. Serum osteocalcin and urinary deoxypyridinoline were measured as biochemical markers of bone turnover. Bones were analyzed by bone histomorphometry and pQCT. RESULTS AND CONCLUSIONS: Our study clearly showed that a dose of estradiol that restores physiological estradiol serum levels, fully maintains uterine weight in OVX rats at the SHAM control level, and suppresses serum follicle-stimulating hormone (FSH) by 67% relative to OVX vehicle controls does not provide significant protection against OVX-induced bone loss at different cancellous and cortical bone sites. We conclude that the long-term sensitivity of the uterus and the hypothalamus/pituitary axis to 17beta-estradiol is higher than that of bone in rats.

Skeletal effects of cyclosporin A are gender related in rats.

The immunosuppressive drug cyclosporin A (CsA) is thought to be involved in the pathogenesis of posttransplantation osteoporosis. To evaluate further the skeletal effects of CsA, we treated aged male and female sham-operated and gonadectomized rats with low doses of CsA for 4 months. Here, we show that CsA is antiresorptive and bone-sparing in aged female rats but increases bone resorption and reduces bone mass in aged male rats. However, even in male rats, CsA treatment, at clinically relevant doses, increased bone resorption only transiently and did not result in pronounced long-term cancellous bone loss. The gender-specific skeletal effects of CsA were not modulated by sex hormones or gonadectomy. CsA did not influence sex steroid metabolism in male or female rats. However, endogenous estradiol in sham-operated female rats (and especially, exogenous administration of 17beta-estradiol in ovariectomized rats) markedly diminished blood levels of CsA, probably by increasing hepatic CsA metabolism. Although the mechanism for the gender-specific skeletal effects of CsA is still obscure, our findings may have important implications for clinical therapy with CsA.