Resistant Hypertension in People With CKD: A Review.

Resistant hypertension is common in the chronic kidney disease population and conveys increased risk for adverse cardiovascular outcomes and the development of kidney failure. Recently, the American College of Cardiology and American Heart Association published a revised scientific statement on the definition and management of resistant hypertension, which codified the long-debated differences between pseudoresistant hypertension and true resistant hypertension. We review this distinction and its importance to nephrologists, who frequently encounter patients for whom antihypertensive therapy fails due to difficulty adhering to complex multidrug regimens. Second, we discuss the evaluation of patients with resistant hypertension, including appropriate screening and diagnostic testing for causes of secondary hypertension. Third, we examine the management of established resistant hypertension, including medication optimization, recent clinical trials supporting lifestyle modifications, and the evidence behind the routine use of mineralocorticoid receptor antagonists. Special attention is given to the vital role of diuretics in the treatment of patients with chronic kidney disease. We propose an algorithm for the diagnosis and management of these cases. Finally, we briefly discuss the current state of antihypertensive device therapies, including kidney denervation and baroreceptor-directed therapies.

A D-amino acid containing peptide as a potent, noncovalent inhibitor of α5ß1 integrin in human prostate cancer invasion and lung colonization.

Primary tumors often give rise to disseminated tumor cells (DTC's), which acquire full malignancy after invading distant site(s). Thus, DTC's may be a productive target for preventing prostate cancer metastasis progression. Our prior research showed that PHSCN peptide (Ac-PHSCN-NH2) targets activated α5ß1 integrin to prevent invasion and metastasis in preclinical adenocarcinoma models, and disease progression in Phase I clinical trial. Here, we report that D-stereoisomer replacement of histidine and cysteine in PHSCN produces a highly potent derivative, Ac-PhScN-NH2 (PhScN). PhScN was 27,000- to 150,000-fold more potent as an inhibitor of basement membrane invasion by DU 145 and PC-3 prostate cancer cells. A large increase in invasion-inhibitory potency occurred after covalent modification of the sulfhydryl group in PHSCN to prevent disulfide bond formation; while the potency of covalently modified PhScN was not significantly increased. Thus PhScN and PHSCN invasion inhibition occurs by a noncovalent mechanism. These peptides also displayed similar cell surface binding dissociation constants (Kd), and competed for the same site. Consistent with its increased invasion-inhibitory potency, PhScN was also a highly potent inhibitor of lung extravasation and colonization in athymic nude mice: it was several hundred- or several thousand-fold more potent than PHSCN at blocking extravasation by PC-3 or DU 145 cells, and 111,000- or 379,000-fold more potent at inhibiting lung colonization, respectively. Furthermore, systemic 5 mg/kg PhScN monotherapy was sufficient to cause complete regression of established, intramuscular DU 145 tumors. PhScN thus represents a potent new family of therapeutic agents targeting metastasis by DTC's to prevent parallel progression in prostate cancer.

Role of α(5)ß(1) Integrin Up-regulation in Radiation-Induced Invasion by Human Pancreatic Cancer Cells.

RADIOTHERAPY IS USED IN THE MANAGEMENT OF PANCREATIC CANCER BECAUSE OF ITS HIGH PROPENSITY FOR LOCOREGIONAL RELAPSE: one third of patients succumb to localized disease. Thus, strategies to improve the efficacy of radiotherapy in pancreatic cancer are important to pursue. We used naturally serum-free, selectively permeable basement membranes and confocal microscopy of fluorescent antibody-stained human Panc-1, MiaPaCa-2, and BxPC-3 pancreatic cancer cell lines to investigate the effects of ionizing radiation on α(5)ß(1) integrin fibronectin receptor expression and on α(5)ß(1)-mediated invasion. We report that radiation rapidly induces pancreatic cancer cell invasion, and that radiation-induced invasion is caused by up-regulation of α(5)ß(1) integrin fibronectin receptors by transcriptional and/or postendocytic recycling mechanisms. We also report that radiation causes α(5)ß(1) up-regulation in Panc-1, MiaPaCa-2, and BxPC-3 tumor xenografts and that upregulated α(5)ß(1) colocalizes with upregulated early or late endosomes in Panc-1 or BxPC-3 tumors, respectively, although it may colocalize significantly with both endosome types in MiaPaCa-2 tumors. Our results suggest that systemic inhibition of α(5)ß(1)-mediated invasion might be an effective way to reduce radiation-induced pancreatic cancer cell invasion, thereby improving the efficacy of radiotherapy.

The PHSCN dendrimer as a more potent inhibitor of human breast cancer cell invasion, extravasation, and lung colony formation.

The α5ß1 integrin fibronectin receptor is an attractive therapeutic target in breast cancer because it plays key roles in invasion and metastasis. While its inactive form is widely expressed, activated α5ß1 occurs only on tumor cells and their associated vasculature. The PHSCN peptide has been shown to bind activated α5ß1 preferentially, thereby blocking invasion in vitro, and inhibiting growth, metastasis and tumor recurrence in preclinical models. Moreover in a recent Phase I clinical trial, systemic PHSCN monotherapy was well tolerated, and metastatic disease failed to progress for 4-14 months in 38% of patients receiving it. A significantly more potent PHSCN derivative, the PHSCN-polylysine dendrimer (Ac-PHSCNGGK-MAP) has recently been developed. We report that it is 1280- to 6700-fold more potent than the PHSCN peptide at blocking α5ß1 mediated SUM-149 PT and MDA-MB-231 human breast cancer cell invasion of naturally occurring basement membranes in vitro. Chou-Talalay analysis of these data suggested that invasion inhibition by the PHSCN dendrimer was highly synergistic. We also report that, consistent with its enhanced invasion-inhibitory potency, the PHSCN dendrimer is 700- to 1100-fold more effective than the PHSCN peptide at preventing SUM-149 PT and MDA-MB-231 extravasation in the lungs of athymic, nude mice. Our results also show that many extravasated SUM-149 PT and MDA-MB-231 cells go on to develop into metastatic colonies, and that pretreatment with the PHSCN dendrimer is more than 100-fold more effective at reducing lung colony formation. Since many patients newly diagnosed with breast cancer already have locally advanced or metastatic disease, the availability of a well-tolerated, nontoxic systemic therapy that can prevent metastatic progression by blocking invasion could be very beneficial.

Increased potency of the PHSCN dendrimer as an inhibitor of human prostate cancer cell invasion, extravasation, and lung colony formation.

Activated alpha5beta1 integrin occurs specifically on tumor cells and on endothelial cells of tumor-associated vasculature, and plays a key role in invasion and metastasis. The PHSCN peptide (Ac-PHSCN-NH(2)) preferentially binds activated alpha5beta1, to block invasion in vitro, and inhibit growth, metastasis and tumor recurrence in preclinical models of prostate cancer. In Phase I clinical trial, systemic Ac-PHSCN-NH(2) monotherapy was well tolerated, and metastatic disease progression was prevented for 4-14 months in one-third of treated patients. We have developed a significantly more potent derivative, the PHSCN-polylysine dendrimer (Ac-PHSCNGGK-MAP). Using in vitro invasion assays with naturally serum-free basement membranes, we observed that the PHSCN dendrimer was 130- to 1900-fold more potent than the PHSCN peptide at blocking alpha5beta1-mediated invasion by DU 145 and PC-3 human prostate cancer cells, whether invasion was induced by serum, or by the Ac-PHSRN-NH(2) peptide, under serum-free conditions. The PHSCN dendrimer was also approximately 800 times more effective than PHSCN peptide at preventing DU 145 and PC-3 extravasation in the lungs of athymic mice. Chou-Talalay analysis suggested that inhibition of both invasion in vitro and extravasation in vivo by the PHSCN dendrimer are highly synergistic. We found that many extravasated DU 145 and PC-3 cells go onto develop into metastatic colonies, and that a single pretreatment with the PHSCN dendrimer was 100-fold more affective than the PHSCN peptide at reducing lung colony formation. Since many patients newly diagnosed with prostate cancer already have locally advanced or metastatic disease, the availability of a well-tolerated, nontoxic systemic therapy, like the PHSCN dendrimer, which prevents metastatic progression by inhibiting invasion, could be very beneficial.

alpha(5)beta(1) Integrin Ligand PHSRN Induces Invasion and alpha(5) mRNA in Endothelial Cells to Stimulate Angiogenesis.

Angiogenesis requires endothelial cell invasion and is crucial for wound healing and for tumor growth and metastasis. Invasion of native collagen is mediated by the alpha(5)beta(1) integrin fibronectin receptor. Thus, alpha(5)beta(1) up-regulation on the surfaces of endothelial cells may induce endothelial cell invasion to stimulate angiogenesis. We report that the interaction of alpha(5)beta(1) with its PHSRN peptide ligand induces human microvascular endothelial cell invasion and that PHSRN-induced endothelial cell invasion is regulated by alpha(4)beta(1) integrin and requires matrix metalloproteinase 1 (MMP-1). Moreover, our results show that exposure to PHSRN causes rapid, specific up-regulation of surface levels of alpha(5)beta(1) integrin and significantly increases alpha(5) integrin mRNA in microvascular endothelial cells. Consistent with these results, alpha(5) small interfering RNA abrogates PHSRN-induced surface alpha(5) and MMP-1 up-regulation, as well as blocking invasion induction. We also observed dose-dependent, PHSRN-induced alpha(5)beta(1) integrin up-regulation on endothelial cells in vivo in Matrigel plugs. We further report that the PHSCN peptide, an alpha(5)beta(1)-targeted invasion inhibitor, blocks PHSRN-induced invasion, alpha(5)beta(1) up-regulation, alpha(5) mRNA induction, and MMP-1 secretion in microvascular endothelial cells and that systemic PHSCN administration prevents PHSRN-induced alpha(5)beta(1) up-regulation and angiogenesis in Matrigel plugs. These results demonstrate a critical role for alpha(5)beta(1) integrin and MMP-1 in mediating the endothelial cell invasion and angiogenesis and suggest that PHSRN-induced alpha(5) transcription and alpha(5)beta(1) up-regulation may form an important feed-forward mechanism for stimulating angiogenesis.