Impaired Interleukin-15 Signaling via Loss Drives Natural Killer Cell Deficiency and Pulmonary Hypertension.

Background: Natural killer (NK) cell impairment is a feature of pulmonary arterial hypertension (PAH) and contributes to vascular remodeling in animal models of disease. Although mutations in , the gene encoding the BMP (bone morphogenetic protein) type-II receptor, are strongly associated with PAH, the contribution of loss to NK cell impairment remains unknown. We explored the impairment of IL (interleukin)-15 signaling, a central mediator of NK cell homeostasis, as both a downstream target of loss and a contributor to the pathogenesis of PAH.

Development of experimental chronic kidney disease and vascular calcification alters diurnal variation of phosphate and its hormonal regulators.

The mineral-bone axis is tightly regulated and dependent on renal function. In chronic kidney disease (CKD) progressive loss of renal capacity disrupts this axis over-time, with marked changes in circulating calcium, phosphate, PTH, and fibroblast growth factor-23 (FGF-23). These changes contribute to the development of cardiovascular disease, like vascular calcification (VC), which worsens morbidity and mortality in CKD.

PTH suppression by calcitriol does not predict off-target actions in experimental CKD.

Vitamin D receptor agonist (VDRA) therapy for PTH suppression is a mainstay for patients with severe CKD. Calcitriol (1,25-(OH) D ) is a former first-line VDRA in CKD treatment. However, a consequence of its use in CKD is accelerated vascular calcification (VC).

Acute Tissue Mineral Deposition in Response to a Phosphate Pulse in Experimental CKD.

Pathogenic accumulation of calcium (Ca) and phosphate (PO ) in vasculature is a sentinel of advancing cardiovascular disease in chronic kidney disease (CKD). This study sought to characterize acute distribution patterns of radiolabeled PO and Ca in cardiovascular tissues of rats with CKD (0.25% dietary adenine).

Calcitriol Accelerates Vascular Calcification Irrespective of Vitamin K Status in a Rat Model of Chronic Kidney Disease with Hyperphosphatemia and Secondary Hyperparathyroidism.

Patients with chronic kidney disease (CKD) have a markedly increased risk for developing cardiovascular disease. Nontraditional risk factors, such as increased phosphate retention, increased serum fibroblast growth factor 23 (FGF-23), and deficiencies in vitamins D and K metabolism, likely play key roles in the development of vascular calcification during CKD progression. Calcitriol [1,25-(OH)-D] is a key transcriptional regulator of matrix Gla protein, a vitamin K-dependent protein that inhibits vascular calcification.

Validation of a routine two-sample iohexol plasma clearance assessment of GFR and an evaluation of common endogenous markers in a rat model of CKD.

Endogenous markers of kidney function are insensitive to early declines in glomerular filtration rate (GFR) and in rodent models, validated, practical alternatives are unavailable. In this study, we determined GFR by modeling the plasma clearance of two compounds, iohexol and inulin, and compared the findings to common endogenous markers. All plasma clearance methods of both iohexol and inulin detected a decline in renal function weeks prior to any increase in endogenous marker.

Calcification of the internal pudendal artery and development of erectile dysfunction in adenine-induced chronic kidney disease: a sentinel of systemic vascular changes.

Introduction: Chronic kidney disease (CKD), erectile dysfunction (ED), and cardiovascular disease share common vascular etiologies and risk factors.

Aim: Using a rat model, this is the first study to characterize the consequences of CKD in the onset and development of ED associated with differential regional vascular calcification and circulatory changes.

Methods: Stable CKD was generated at 3 weeks in male Sprague-Dawley rats given dietary adenine and progressed until 7 weeks.

Pathologic mechanisms of type 1 VWD mutations R1205H and Y1584C through in vitro and in vivo mouse models.

Type 1 VWD is the mild to moderate reduction of VWF levels. This study examined the mechanisms underlying 2 common type 1 VWD mutations, the severe R1205H and more moderate Y1584C. In vitro biosynthesis was reduced for both mutations in human and mouse VWF, with the effect being more severe in R1205H.

Mutation-specific hemostatic variability in mice expressing common type 2B von Willebrand disease substitutions.

Type 2B von Willebrand disease (2B VWD) results from von Willebrand factor (VWF) A1 mutations that enhance VWF-GPIbalpha binding. These "gain of function" mutations lead to an increased affinity of the mutant VWF for platelets and the binding of mutant high-molecular-weight VWF multimers to platelets in vivo, resulting in an increase in clearance of both platelets and VWF. Three common 2B VWD mutations (R1306W, V1316M, and R1341Q) were independently introduced into the mouse Vwf cDNA sequence and the expression vectors delivered to 8- to 10-week-old C57Bl6 VWF(-/-) mice, using hydrodynamic injection.