Forskolin Modulate Silent Information Regulator 1 (SIRT1) gene Expression and Halts Experimentally-Induced Acute Kidney Injury

Abstract

Acute kidney injury is a very serious medical condition; change of the normal physiological oxidant-antioxidant balance has been reported as a major cause for renal injury. Silent information regulator 1 (Sirt1) is a nicotinamide adenine dinucleotide- (NAD+-) dependent deacetylase that has nephro-protective effect against ischemia or injury by toxic substances by increasing cell resistance to oxidative stress. Forskolin is derived from plant Coleus forskohlii and has been used to treat the heart disease, hypertension, diabetes and asthma. This study was done to investigate the possible protective role of forskolin against glycerol- induced acute nephrotoxicity and also to study the possible mechanisms underlying this action. In the present study rats were randomly divided into four groups. Rats in the control group received distilled water orally for 15 days, four days before scarification they received half the dose of saline (10 ml/kg) in each hind limb muscle; rats in the FSK group received 500 mg/kg per day, orally for 15 days; those in the glycerol group (AKI) received half the dose of glycerol (10 ml/kg, 50% v/v in sterile saline) in each hind limb muscle; rats in the FSK + glycerol (AKI) group received FSK 500 mg/kg per day, orally 12 days before glycerol injection and continued for three days after glycerol administration with a total period of 15 days, all rats were deprived of water for 24 h before glycerol injection. Parameters tested in this study were kidney function tests (urea, creatinine), oxidative stress parameters (MDA, GST), anti-inflammatory marker (TNF-α), anti-apoptotic marker (caspase-3), SIRT gene expression detected by RT-PCR and histopathlogical study. Results: Glycerol administration caused significant increase in all tested parameters except SIRT gene expression which decreased with glycerol administration. Pretreatment with forskolin caused significant decrease of levels of urea, creatinine, MDA, TNF-α and also decreased activity of caspase-3 and GST, with significant improvement of SIRT expression. Histopathological examination revealed that the glycerol caused severe kidney damage in the form of hemorrhage, inflammatory cell infiltration and intra-tubular cast formation compared to normal renal histology and architecture of the control and forskolin groups. Forskolin pretreatment of glycerol induced AKI caused marked improvement of histological picture which exhibited mild edema and tubular vacuolization compared to the control group. In conclusion the possible beneficial effect of forskolin in protection against nephrotoxicity is due to its ability to modulate the disrupted expression of SIRT gene as well as its anti-oxidant, anti-inflammatory and anti-apoptotic properties. This may open a new therapeutic window for renal patient.