Non-alcoholic fatty liver disease (NAFLD) is an increasingly
common disorder and a major global burden, affecting up to 30% of the
general population and approximately 80% of obese individuals. NAFLD
is frequently associated with the metabolic syndrome including diabetes
mellitus, hypercholesterolemia and obesity.
Risk factors for NAFLD include obesity, type 2 diabetes,
hyperlipidemia, total parenteral nutrition, jejuno-ileal bypass surgery and
the use of certain drugs.
NAFLD includes a wide spectrum of liver clinicopathologic
conditions, ranging from pure fatty steatosis (fatty infiltration in >5% of
hepatocytes) which is apparently a benign condition to nonalcoholic
steatohepatitis (NASH), which may progress to cirrhosis, liver failure,
and hepatocellular carcinoma (HCC).
Drug-induced nephrotoxicity is an extremely common condition
and is responsible for a variety of pathological effects on the kidneys. It is
defined as renal disease or dysfunction that arises as a direct or indirect
result of exposure to drugs.
The kidney receives 21% of the cardiac output and plays an
important role in the elimination of many drugs and their metabolites.
The kidney is therefore exposed to high concentrations of drugs and
metabolites, making it vulnerable to drug toxicity. It is therefore not
surprising that drug-induced renal injury contributes up to 20% of all
cases of acute renal failure.
Most drugs found to cause nephrotoxicity exert toxic effects by one
or more common pathogenic mechanisms. These include altered
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intraglomerular hemodynamics, tubular cell toxicity, inflammation,
crystal nephropathy, rhabdomyolysis and thrombotic microangiopathy.
Gentamicin (GM) is considered as one of the aminoglycoside
antibiotics used to treat life threatening gram-negative bacteria.
Nephrotoxicity is one of the most important side effects of the use of
gentamicin resulted in reactive oxygen species (ROS) generation such as
superoxide anion, hydrogen peroxide and hydroxyl radicals in the kidney.
The renin-angiotensin system (RAS) is one of the major regulators
of blood pressure; fluid and electrolyte homeostasis. The RAS was
originally regarded as a circulating system, however, many of its
components are localized in tissues indicating the existence of a local
tissue RAS. The RAS antagonists are effective and safe antihypertensive
drugs. These drugs have demonstrated additional hepatic and renal
protective effects to their blood pressure lowering effect.
Captopril is an orally active specific competitive inhibitor of ACE.
Irbesartan is a direct acting non peptide selective AT1 receptor antagonist.
Both drugs are indicated in cases of hypertension, ischemic heart diseases
and congestive heart failure.
The present study was carried out to compare the hepatic and renal
protective effects of these drugs on experimentally induced fatty liver and
nephrotoxicity in adult male rats.
24 rats were used to estimate the potential hepatoprotective effect
of administration of captopril (100mg/kg/day orally) versus irbesartan
(30mg/kg/day orally) on high fat diet (HFD) (1% cholesterol+10%
coconut oil) induced fatty liver. Rats were divided into 4 equal groups.
Control group (group I): received standard chow diet with no medication,
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fatty liver untreated group (group II): received HFD via oral gavage for 8
weeks, irbesartan pretreated group (group III): received HFD+ irbesartan
for 8 weeks and captopril pretreated group (group IV): received HFD+
captopril for 8 weeks. It was found that HFD produced significant
elevation of liver enzymes, total cholesterol, triglycerides and LDL-c and
significant reduction of HDL-c, A/G ratio, PT and serum reduced
glutathione, Both drugs produced significant reduction of liver enzymes,
total cholesterol, triglycerides and LDL-c and significant elevation of
HDL-c, A/G ratio and serum reduced glutathione, Both drugs have no
effect on PT and both drugs improved liver pathology induced by HFD.
Another 24 rats were used to investigate the possible
renoprotective effect of captopril versus irbesartan on gentamicin induced
nephrotoxicity. Rats were divided into 4 groups. Group I: is control group
was fed with standard diet with no medication. Group II: received
gentamicin 100mg/kg/day intraperitonial (i.p.) for 12 days. Group III:
received gentamicin100mg/kg/day i.p. concomitantly with irbesartan
25mg/kg/day orally for 12 days. Group IV: received
gentamicin100mg/kg/day i.p. concomitantly with captopril 50mg/kg/day
orally for 12 days. Data revealed that gentamicin increased serum urea,
serum creatinine, 24 hrs urinary protein excretion and decreased serum
reduced glutathione (GSH) significantly compared with control. Renal
damage was confirmed by histopathological studies. Both irbesartan and
captopril treatment decreased serum urea, serum creatinine, 24 hrs
urinary protein excretion and increased serum reduced glutathione (GSH)
significantly compared with gentamicin group, also histopathology of the
kidney was improved.
Captopril affords better hepatoprotective effect as regard liver
enzymes, total cholesterol, triglycerides, LDL-c, A/G ratio and liver
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histopathology than irbesartan and also better renoprotective effect as
regard serum urea, serum creatinine, 24 hrs urinary protein excretion and
histopathological examination of the kidney than irbesartan, while there
was insignificant difference in serum GSH and HDL-c between both
drugs.
From previous data one may assume that (conclusions):
The renin-angiotensin system plays an important role in
pathogenesis of hypertension, congestive heart failure, fatty liver and
nephrotoxicity. Inhibition of RAS by either ACEI or ARBs may have a
protective effect on liver and kidney in addition to its effect on systemic
blood vessels and heart.
Clinically such findings may suggest the use of drugs acting on
RAS in patients prone to develop fatty liver (e.g. viral hepatitis C,
obesity, hyperlipidemia and Diabetes) or/and nephrotoxicity, particularly
if these patients have any cardiovascular disease (e.g. hypertension,
congestive heart failure, post myocardial infarction).
Proposal for future research:
Further studies on the effects of captopril and irbesartan in
experimental animal models to reveal other possible
hepatoprotective and renoprotective mechanisms.
Further studies are needed to find out the hepatic and renal
protective effects of captopril and irbesartan while changing the
administration duration and the dosage used.
Further experimental and clinical studies are needed for confirming
effectiveness and safety. |
