13 research outputs found
Inhibition of estradiol synthesis attenuates renal injury in male streptozotocin-induced diabetic rats
Combined inhibition of aromatase activity and dihydrotestosterone supplementation attenuates renal injury in male streptozotocin (STZ)-induced diabetic rats
Sex differences in vasopressin V2 receptor expression and vasopressin-induced antidiuresis
The renal vasopressin V2 receptor (V2R) plays a critical role in physiological and pathophysiological processes associated with arginine vasopressin (AVP)-induced antidiuresis. Because clinical data suggests that females may be more prone to hyponatremia from AVP-mediated antidiuresis, we investigated whether there are sex differences in the expression and function of the renal V2R. In normal Sprague-Dawley rat kidneys, V2R mRNA and protein expression was 2.6- and 1.7-fold higher, respectively, in females compared with males. To investigate the potential physiological implications of this sex difference, we studied changes in urine osmolality induced by the AVP V2R agonist desmopressin. In response to different doses of desmopressin, there was a graded increase in urine osmolality and decrease in urine volume during a 24-h infusion. Females showed greater mean increases in urine osmolality and greater mean decreases in urine volume at 0.5 and 5.0 ng/h infusion rates. We also studied renal escape from antidiuresis produced by water loading in rats infused with desmopressin (5.0 ng/h). After 5 days of water loading, urine osmolality of both female and male rats escaped to the same degree physiologically, but V2R mRNA and protein in female kidneys was reduced to a greater degree (â63% and â73%, respectively) than in males (â32% and â48%, respectively). By the end of the 5-day escape period, renal V2R mRNA and protein expression were reduced to the same relative levels in males and females, thereby abolishing the sex differences in V2R expression seen in the basal state. Our results demonstrate that female rats express significantly more V2R mRNA and protein in kidneys than males, and that this results physiologically in a greater sensitivity to V2R agonist administration. The potential pathophysiological implications of these results are that females may be more susceptible to the development of dilutional hyponatremia because of a greater sensitivity to endogenously secreted AVP
DIAPH1 mediates progression of atherosclerosis and regulates hepatic lipid metabolism in mice
Funding for this project included: U.S. Public Health Service (P01HL146367) to AMS, AS, and RR and 1P01HL131481 (EF, AMS, and RR). Support was also provided from the Diabetes Research Program, NYU Grossman School of Medicine.
Primary data are available in Supplementary Data 1â6. RNAseq data are deposited to NCBI GEO GSE156403. Any materials reported in this research are available through Material Transfer Agreement (MTA) with NYU Grossman School of Medicine.Atherosclerosis evolves through dysregulated lipid metabolism interwoven with exaggerated inflammation. Previous work implicating the receptor for advanced glycation end products (RAGE) in atherosclerosis prompted us to explore if Diaphanous 1 (DIAPH1), which binds to the RAGE cytoplasmic domain and is important for RAGE signaling, contributes to these processes. We intercrossed atherosclerosis-prone Ldlrâ/â mice with mice devoid of Diaph1 and fed them Western diet for 16 weeks. Compared to male Ldlrâ/â mice, male Ldlrâ/â Diaph1â/â mice displayed significantly less atherosclerosis, in parallel with lower plasma concentrations of cholesterol and triglycerides. Female Ldlrâ/â Diaph1â/â mice displayed significantly less atherosclerosis compared to Ldlrâ/â mice and demonstrated lower plasma concentrations of cholesterol, but not plasma triglycerides. Deletion of Diaph1 attenuated expression of genes regulating hepatic lipid metabolism, Acaca, Acacb, Gpat2, Lpin1, Lpin2 and Fasn, without effect on mRNA expression of upstream transcription factors Srebf1, Srebf2 or Mxlipl in male mice. We traced DIAPH1-dependent mechanisms to nuclear translocation of SREBP1 in a manner independent of carbohydrate- or insulin-regulated cues but, at least in part, through the actin cytoskeleton. This work unveils new regulators of atherosclerosis and lipid metabolism through DIAPH1.Depto. de GenĂ©tica, FisiologĂa y MicrobiologĂaFac. de Ciencias BiolĂłgicasTRUEpu