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Renoprotective effects of the direct renin inhibitor aliskiren on gentamicin-induced nephrotoxicity in rats.
- Source :
-
Journal of the renin-angiotensin-aldosterone system : JRAAS [J Renin Angiotensin Aldosterone Syst] 2014 Dec; Vol. 15 (4), pp. 348-61. Date of Electronic Publication: 2013 Feb 18. - Publication Year :
- 2014
-
Abstract
- This study aimed to examine the protective effects of aliskiren on gentamicin-induced nephropathy. Rats were injected with gentamicin (100 mg/kg per day) for 14 days. Aliskiren was infused for two weeks. Human proximal tubular epithelial cell lines (HK-2) were cultured with gentamicin in the absence or presence of aliskiren. Inflammatory profibrotic and apoptotic markers were evaluated in vivo and in vitro. Aliskiren treatment attenuated the decreased creatinine clearance, increased fractional sodium excretion, glomerulosclerosis and tubulointerstitial fibrosis and counteracted the increased ED-1 expression in gentamicin-treated rats. The levels of inflammatory cytokines (TNF-α, IL-1β and IFN-γ) and adhesion molecules (MCP-1, ICAM-1 and VCAM-1) increased in the gentamicin-treated kidneys. These changes were restored by aliskiren co-treatment. Aliskiren effectively reversed transforming growth factor-β-induced fibrotic responses such as induction of α-smooth muscle actin in gentamicin-treated rat kidneys. Along with these changes, aliskiren also attenuated the increase in nuclear factor κB and phosphorylated extracellular signal-regulated kinase (pERK 1/2) levels in HK-2 cells cultured with gentamicin. In addition, aliskiren decreased the number of TUNEL-positive nuclei and reduced the expression of proapoptotic markers in gentamicin-treated HK-2 cells. These findings suggest that aliskiren attenuates gentamicin-induced nephropathy by suppression of inflammatory, profibrotic and apoptotic factors through inhibition of the nuclear factor κB, Smads and mitogen-activated protein kinase signaling pathways.<br /> (© The Author(s) 2013.)
- Subjects :
- Amides pharmacology
Animals
Apoptosis drug effects
Cell Adhesion Molecules metabolism
Cytokines genetics
Cytokines metabolism
Extracellular Signal-Regulated MAP Kinases metabolism
Fibrosis
Fumarates pharmacology
Humans
Immunoblotting
Inflammation Mediators metabolism
Kidney drug effects
Kidney enzymology
Kidney pathology
Kidney physiopathology
Kidney Diseases pathology
Kidney Diseases physiopathology
Kidney Function Tests
Kidney Tubules drug effects
Kidney Tubules pathology
Male
NF-kappa B metabolism
Protective Agents pharmacology
Proton-Translocating ATPases metabolism
Rats, Sprague-Dawley
Real-Time Polymerase Chain Reaction
Receptors, Cell Surface metabolism
Renin metabolism
Smad Proteins metabolism
Transforming Growth Factor beta1 metabolism
Vacuolar Proton-Translocating ATPases
bcl-2-Associated X Protein metabolism
Amides therapeutic use
Fumarates therapeutic use
Gentamicins adverse effects
Kidney Diseases chemically induced
Kidney Diseases drug therapy
Protective Agents therapeutic use
Renin antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1752-8976
- Volume :
- 15
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Journal of the renin-angiotensin-aldosterone system : JRAAS
- Publication Type :
- Academic Journal
- Accession number :
- 23420778
- Full Text :
- https://doi.org/10.1177/1470320312474853