Renoprotective effects of the direct renin inhibitor aliskiren on gentamicin-induced nephrotoxicity in rats.

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.

• Authors: Eun Hui Bae, In Jin Kim, Soo Yeon Joo, Eun Young Kim, Joon Seok Choi, Chang Seong Kim, Seong Kwon Ma, JongUn Lee, Soo Wan Kim
• Journal: Journal of the renin-angiotensin-aldosterone system : JRAAS (J Renin Angiotensin Aldosterone Syst) Vol. 15 Issue 4 Pg. 348-61 (Dec 2014) ISSN: 1752-8976 [Electronic] England
• PMID: 23420778 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2013.

Chemical References

• Amides
• Cell Adhesion Molecules
• Cytokines
• Fumarates
• Gentamicins
• Inflammation Mediators
• NF-kappa B
• Protective Agents
• Receptors, Cell Surface
• Smad Proteins
• Transforming Growth Factor beta1
• bcl-2-Associated X Protein
• aliskiren
• Extracellular Signal-Regulated MAP Kinases
• Renin
• ATP6AP2 protein, rat
• Vacuolar Proton-Translocating ATPases
• Proton-Translocating ATPases

Topics

• Amides (pharmacology, therapeutic use)
• Animals
• Apoptosis (drug effects)
• Cell Adhesion Molecules (metabolism)
• Cytokines (genetics, metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Fibrosis
• Fumarates (pharmacology, therapeutic use)
• Gentamicins (adverse effects)
• Humans
• Immunoblotting
• Inflammation Mediators (metabolism)
• Kidney (drug effects, enzymology, pathology, physiopathology)
• Kidney Diseases (chemically induced, drug therapy, pathology, physiopathology)
• Kidney Function Tests
• Kidney Tubules (drug effects, pathology)
• Male
• NF-kappa B (metabolism)
• Protective Agents (pharmacology, therapeutic use)
• Proton-Translocating ATPases (metabolism)
• Rats, Sprague-Dawley
• Real-Time Polymerase Chain Reaction
• Receptors, Cell Surface (metabolism)
• Renin (antagonists & inhibitors, metabolism)
• Smad Proteins (metabolism)
• Transforming Growth Factor beta1 (metabolism)
• Vacuolar Proton-Translocating ATPases
• bcl-2-Associated X Protein (metabolism)