Abstract-Genetic dissection of the rat genome for identifying alleles that cause abnormalities in blood pressure (BP) resulted in the mapping of a significant number of BP quantitative trait loci (QTLs). In this study we mapped at least one such BP QTL on rat chromosome 10 (RNO10) as being within the introgressed segment of a S.LEW congenic strain S.LEWx12x2x3x8 spanning 1.34 Mb from 70 725 437 bp to 72 063 232 bp. BP of 3 congenic strains that span shorter segments of this region was additionally examined. Results obtained indicate that LEW alleles that comprise a 375-kb introgressed segment of the congenic strain S.LEWx12x2x3x5 (70 725 437 bp to 71 100 513 bp) increase BP. The magnitude of change in BP exhibited by the 2 strains, S.LEWx12x2x3x8 and S.LEWx12x2x3x5, is the net phenotypic effect of the underlying genetic determinants of BP. In this respect, the current data are superior to previous QTL localization of BP QTL1, which was hypothesized based on differential congenic segments. Genetic dissection using these 2 congenic strains as tools is expected to facilitate further dissection of the regions. Meanwhile, differential congenic segments were used to predict and thereby prioritize regions for candidate gene analysis. Using this approach, 2 distinct regions of 401 kb and 409 kb within S.LEWx12x2x3x8 and a 104 kb region within S.LEWx12x2x3x5 were prioritized for further consideration. Because all of these genetic elements are located within a 1.06-Mb region of RNO10, our study has revealed a remarkable insight into a genomic module comprising very closely-linked, opposing genetic determinants of BP. espite the description of a number of blood pressure (BP) quantitative trait loci (QTLs) in humans, rats, and mice, identities of the underlying genetic determinants conferring susceptibility to hypertension in any species remain largely unknown, [1][2][3][4] with the exception of rat 11-␤-hydroxylase 5,6 and CD36. 7 Linkage analysis and substitution mapping using various rat strain comparisons provide conclusive evidence for the existence of multiple genetic determinants of BP on rat chromosome 10 (RNO10). 8 -32 Located on this chromosome are genes coding for angiotensin-I converting enzyme, nerve growth factor receptor, skeletal myosin heavy polypeptide 3, nitric oxide synthase-2, ATPase-Na ϩ /K ϩ transporting-␤ 2 polypeptide, nicotiniccholinergic receptor-beta polypeptide 1, and protein kinaselysine deficient 4, all of which are appealing candidates for causally controlling BP. However, fine-mapping and/or DNA sequencing has not provided evidence for most of these genes as candidates for BP QTLs, implicating that the identities of the genetic determinants of BP on RNO10 remain elusive. 8 -31 By replacing progressively shorter segments of RNO 10 of the hypertensive Dahl Salt-sensitive (S) rat with corresponding segments from the Lewis (LEW) rat genome, we have previously fine-mapped a BP quantitative trait locus (S.LEW BP QTL1) to a 1.17-Mb region containing 18 genes. 32 None of these genes have any kn...

Management of metabolic acidosis covers the entire spectrum from oral bicarbonate therapy and dietary modifications in chronic kidney disease to delivery of high doses of bicarbonate-based dialysate during maintenance haemodialysis (MHD). Due to the gradual depletion of the body's buffers and rapid repletion during MHD, many potential problems arise as a result of our current treatment paradigms. Several studies have given rise to conflicting data about the adverse effects of our current practice patterns in MHD. In this review, we will describe the pathophysiology and consequences of metabolic acidosis and its therapy in CKD and ESRD, and discuss current evidence supporting a more individualized approach for bicarbonate therapy in MHD.

Binding of ouabain to cardiac Na/K-ATPase initiates cell signaling and causes contractility in cardiomyocytes. It is widely accepted that caveolins, structural proteins of caveolae, have been implicated in signal transduction. It is known that caveolae play a role in Na/K-ATPase functions. Regulation of caveolin-1 in ouabain-mediated cardiac signaling and contractility has never been reported. The aim of this study is to compare ouabain-induced cardiac signaling and contractility in wild-type (WT) and caveolin-1 knockout (cav-1 KO) mice. In contrast with WT cardiomyocytes, ouabain-induced signaling e.g., activation of phosphoinositide 3-kinase-α/Akt and extracellular signal-regulated kinases (ERK)1/2, and hypertrophic growth were significantly reduced in cav-1 KO cardiomyocytes. Interactions of the Na/K-ATPase α-subunit with caveolin-3 and the Na/K-ATPase α-subunit with PI3K-α were also decreased in cav-1 KO cardiomyocytes. The results from cav-1 KO mouse embryonic fibroblasts also proved that cav-1 significantly attenuated ouabain-induced ERK1/2 activation without alteration in protein and cholesterol distribution in caveolae/lipid rafts. Intriguingly, the effect of ouabain induced positive inotropy in vivo (via transient infusion of ouabain, 0.48 nmol/g body wt) was not attenuated in cav-1 KO mice. Furthermore, ouabain (1-100 μM) induced dose-dependent contractility in isolated working hearts from WT and cav-1 KO mice. The effects of ouabain on contractility between WT and cav-1 KO mice were not significantly different. These results demonstrated differential roles of cav-1 in the regulation of ouabain signaling and contractility. Signaling by ouabain, in contrast to contractility, may be a redundant property of Na/K-ATPase.

Angiotensin II (Ang II) causes nitric oxide synthase (NOS) to become a source of superoxide (O2 −) via a protein kinase C (PKC)‐dependent process in endothelial cells. Ang II stimulates both NO and O2 − production in thick ascending limbs. We hypothesized that Ang II causes O2 − production by NOS in thick ascending limbs via a PKC‐dependent mechanism. NO production was measured in isolated rat thick ascending limbs using DAF‐FM, whereas O2 − was measured in thick ascending limb suspensions using the lucigenin assay. Consistent stimulation of NO was observed with 1 nmol/L Ang II (P < 0.001; n = 9). This concentration of Ang II‐stimulated O2 − production by 50% (1.77 ± 0.26 vs. 2.62 ± 0.36 relative lights units (RLU)/s/μg protein; P < 0.04; n = 5). In the presence of the NOS inhibitor L‐NAME, Ang II‐stimulated O2 − decreased from 2.02 ± 0.29 to 1.10 ± 0.11 RLU/s/μg protein (P < 0.01; n = 8). L‐arginine alone did not change Ang II‐stimulated O2 − (2.34 ± 0.22 vs. 2.29 ± 0.29 RLU/s/μg protein; n = 5). In the presence of Ang II plus the PKC α/β 1 inhibitor Gö 6976, L‐NAME had no effect on O2 − production (0.78 ± 0.23 vs. 0.62 ± 0.11 RLU/s/μg protein; n = 7). In the presence of Ang II plus apocynin, a NADPH oxidase inhibitor, L‐NAME did not change O2 − (0.59 ± 0.04 vs. 0.61 ± ×0.08 RLU/s/μg protein; n = 5). We conclude that: (1) Ang II causes NOS to produce O2 − in thick ascending limbs via a PKC‐ and NADPH oxidase‐dependent process; and (2) the effect of Ang II is not due to limited substrate.

IN BRIEF Treatment guidelines for diabetic emergencies are well described in patients with normal to moderately impaired kidney function. However, management of patients with end-stage renal disease (ESRD) is an ongoing challenge. This article describes a retrospective study comparing the rates of adverse glucose events (defined as hypoglycemia or a decrease in glucose >200 mg/dL/h) between patients with ESRD and those with normal kidney function who were admitted with diabetic ketoacidosis (DKA) or hyperosmolar hyperglycemic state (HHS). These results indicate that current treatment approaches to DKA or HHS in patients with ESRD are suboptimal and require further evaluation.