aliskiren and Nephrosclerosis

The aim of this study was to investigate the antialbuminuric and antihypertensive effects of aliskiren by monitoring home blood pressure (BP) in comparison with the effects of the angiotensin receptor blocker (ARB) valsartan in patients with hypertensive nephrosclerosis and albuminuria.. We conducted an open-label, randomized trial to compare the effects of aliskiren with those of valsartan. Patients with BP <150/90 mmHg, an estimated glomerular filtration rate of 90-30 mL/min/1.73 m(2), and albuminuria >30 mg/g, despite treatment with a 160 mg daily dose of valsartan, were randomly assigned to the following two groups: the aliskiren group, who switched from 160 mg/day valsartan to 150 mg/day aliskiren, which was later increased to 300 mg/day (n = 20); and the valsartan group, who continued with 160 mg/day valsartan (n = 20).. After 12 weeks of treatment, although there was no significant difference in clinic BP between groups, a significant reduction in morning and evening systolic BP was observed in the aliskiren group. The decrease in albuminuria in the aliskiren group was significantly better than that in the valsartan group, and a significant correlation was noted between the change in morning systolic BP and the change in albuminuria in the aliskiren group (r = 0.564, P = 0.0084).. We showed that aliskiren treatment leads to a greater reduction in albuminuria and home systolic BP values than valsartan in patients with nephrosclerosis. We propose that aliskiren therapy should be considered as a therapeutic modality to complement ARBs in hypertensive patients with nephrosclerosis.

Topics: Adult; Aged; Albuminuria; Amides; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Female; Fumarates; Humans; Hypertension; Hypertension, Renal; Male; Middle Aged; Nephritis; Nephrosclerosis; Tetrazoles; Valine; Valsartan

We have demonstrated that mesenchymal cells from spontaneously hypertensive rats genetically express complement 3 (C3). Mature tubular epithelial cells can undergo epithelial-to-mesenchymal transition (EMT) that is linked to the pathogenesis of renal fibrosis and injury. In this study, we investigated the contribution of C3 in EMT and in the renal renin-angiotensin (RA) systems associated with hypertension. C3a induced EMT in mouse TCMK-1 epithelial cells, which displayed increased expression of renin and Krüppel-like factor 5 (KLF5) and nuclear localization of liver X receptor α (LXRα). C3 and renin were strongly stained in the degenerated nephrotubulus and colocalized with LXRα and prorenin receptor in unilateral ureteral obstruction (UUO) kidneys from wild-type mice. In C3-deficient mice, hydronephrus and EMT were suppressed, with no expression of renin and C3. After UUO, systolic blood pressure was increased in wild-type but not C3-deficient mice. In wild-type mice, intrarenal angiotensin II (ANG II) levels were markedly higher in UUO kidneys than normal kidneys and decreased with aliskiren. There were no increases in intrarenal ANG II levels after UUO in C3-deficient mice. Thus C3 induces EMT and dedifferentiation of epithelial cells, which produce renin through induction of LXRα. These data indicate for the first time that C3 may be a primary factor to activate the renal RA systems to induce hypertension.

Topics: Aldosterone; Amides; Angiotensin II; Animals; Antihypertensive Agents; Complement C3; Epithelial-Mesenchymal Transition; Fumarates; Hypertension; Kidney; Kruppel-Like Transcription Factors; Liver X Receptors; Male; Mice; Mice, Inbred C57BL; Nephrosclerosis; Orphan Nuclear Receptors; Renin; Renin-Angiotensin System; Transforming Growth Factor beta1; Ureteral Obstruction