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Montréal, Canada

Burke G.M.,Boston University | Sica D.A.,Div. of Nephrology | Sica D.A.,University of Richmond | Frishman W.H.,New York Medical College
Cardiology in Review | Year: 2012

Systemic hypertension is a common cardiovascular problem that often cannot be fully treated with existing nonpharmacologic and pharmacologic measures. A catheter-based strategy which denervates the renal afferent and efferent autonomic nervous system has been developed for the treatment of drug-resistant hypertension. In early clinical trials, this procedure was shown to be both feasible and safe in reducing blood pressure in patients with uncontrolled hypertension receiving treatment with a minimum of 3 antihypertensive drugs. In addition, this procedure has been associated with decreased renin secretion, preservation of renal function, improved glucose tolerance, and a reduction in left ventricular hypertrophy. The long-term effects of this procedure (beyond 3 years) still need to be determined. A large 530-patient sham-controlled trial is now in progress. Copyright © 2012 by Lippincott Williams & Wilkins. Source

Wu W.-P.,China Medical University at Taichung | Chang C.-H.,National Yang Ming University | Chiu Y.-T.,Taichung Veterans General Hospital | Ku C.-L.,Chang Bing Show Chwan Memorial Hospital | And 6 more authors.
American Journal of Physiology - Renal Physiology | Year: 2010

The protective effect of combination therapy with valsartan and aliskiren against renal fibrosis remains to be defined. This study was undertaken to examine the protective effects of the combination of valsartan and aliskiren against renal fibrosis induced by unilateral ureteral obstruction (UUO). Combination therapy with valsartan (15 mg·kg-1·day -1) and aliskiren (10 mg·kg-1·day -1), valsartan monotherapy (30 mg·kg -1·day-1), and aliskiren monotherapy (20 mg·kg-1·day-1) all significantly ameliorated the increase in blood urea nitrogen and the degree of hydronephrosis determined by the increase in weight and length of the obstructed kidney. The dose titration study and blood pressure measurement confirmed that the combination therapy provided a greater benefit independent of the vasodilatory effect. There were no significant changes in serum levels of creatinine, sodium, and potassium in UUO rats and any treatment groups. Combination therapy also attenuated UUO-related increases in the scores of tubular dilatation, interstitial volume, interstitial collagen deposition, α-smooth muscle actin, the activation of ERK 1/2, the infiltration of monocytes/macrophages, the mRNA expression of snail-1, and transforming growth factor-β1 to a greater extent compared with aliskiren or valsartan used alone. The mRNA expression of renin and the (pro)renin receptor significantly increased after UUO. Combination therapy and monotherapy of valsartan and aliskiren had a comparable enhancing effect on the mRNA expression of renin, whereas all these treatments did not affect the expression of the (pro)renin receptor. In conclusion, a direct renin inhibitor in conjunction with an angiotensin II receptor blocker exerts increased renal protection against renal fibrosis and inflammation during obstruction over either agent alone. Copyright © 2010 the American Physiological Society. Source

Cybulsky A.V.,Div. of Nephrology | Takano T.,Div. of Nephrology | Papillon J.,Div. of Nephrology | Kitzler T.M.,Div. of Nephrology | Bijian K.,Div. of Nephrology
American Journal of Physiology - Renal Physiology | Year: 2011

Focal segmental glomerulosclerosis (FSGS) may be associated with glomerular epithelial cell (GEC; podocyte) apoptosis due to acquired injury or mutations in specific podocyte proteins. This study addresses mediation of GEC injury, focusing on endoplasmic reticulum (ER) stress. We studied signaling in cultured GECs in the presence or absence of the extracellular matrix (ECM). Adhesion to collagen supports cell survival, but adhesion to plastic (loss of contact with ECM) leads to apoptosis. Compared with collagen-adherent cells, GECs on plastic showed increased protein misfolding in the ER, and an adaptiveprotective ER stress response, including increased expression of ER chaperones, increased phosphorylation of eukaryotic translation initiation factor-2α (eIF2α), and a reduction in protein synthesis. Activation of these ER stress pathways counteracted apoptosis. However, tunicamycin (a potent stimulator of ER stress) changed the ER stress response from protective to cytotoxic, as tunicamycin induced the proapoptotic ER stress gene, C/EBP homologous protein-10, and exacerbated apoptosis in GECs adherent to plastic, but not collagen. In GECs adherent to plastic, adaptive ER stress was associated with an increase in polyubiquitinated proteins and "choking" of the proteasome. Furthermore, pharmacological inhibition of the proteasome induced ER stress in GECs. Finally, we show that ER stress (induction of ER chaperones and eIF2α phosphorylation) was evident in experimental FSGS in vivo. Thus interactions of GECs with ECM may regulate protein folding and induction of the ER stress response. FSGS is associated with induction of ER stress. Enhancing protective aspects of the ER stress response may reduce apoptosis and possibly glomerulosclerosis. © 2011 the American Physiological Society. Source

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