4. Discussions
GM is an effective aminoglycoside antibiotic widely prescribed for the
treatment of infections, but its adverse effects associated with
oxidative stress and kidney damage limit its long-term clinical use3. The beginning of renal failure and the increase of
serum creatinine is usually slow. Serum creatinine and blood urea
nitrogen characteristically increase 7-10 days after the start of
aminoglycoside therapy 22. Especially in elderly
individuals, a long time is required to treat GM-induced nephrotoxicity.
Although most patients recover, the presence of certain risk factors may
change the clinical picture or course. The recovery in kidney function
may not completely improve in individuals with pre-existing chronic
kidney disease 23. The side effects of GM are great
importance to reduce for those reasons.
α-GST is an enzyme that has an important role in scavenging free
radicals and reducing kidney damage. It was determined that α-GST level
increased due to damage in the proximal tubules in the kidneys of rats
in which GM was administered for 5 days 24. The urine
biomarker such as IL-18, NGAL and KIM-1 is important for the early
diagnosis of acute renal failure. Inflammatory cytokines (IL-1β, IL-6,
IL-18 and TNF-α) and proteins that protect renal tubular cells such as
NGAL and KIM-1 are released in the renal response by GM induced kidney
damage 25. Although serum BUN and creatinine levels
observed to be unchanged on the 4th day after GM (100 mg/kg)
application, KIM-1 and NGAL levels increased 26. In
case of exposure to antibiotics or environmental toxic substances,
urinary RBP increases due to renal tubule dysfunction27. Resatorvid (5 mg/kg and 10 mg/kg doses) treatment
has been reported to protect tissues against ischemia by inhibiting
oxidative stress (MDA), TLR4 pathway and expression of IL-18, oxidative
stress and apoptosis 9,10. ALA treatment (50 mg/kg)
had a protective effect by preventing tubular damage with antioxidant
effects in rabbits with GM-induced experimental nephrotoxicity28.
GST reduces the effectiveness of substances that cause renal toxicity
due to it being conjugated with glutathione. ALA has high singlet oxygen
binding capacity and prevents lipid peroxidation. Moreover, it
accelerates tissue regeneration by reducing oxidative stress. It has
been reported that ALA scavenges free oxygen radicals and increases SOD,
CAT, GPx and GST activities in rats with experimental nephrotoxicity29. ALA by the antioxidant effects decreased KIM-1
expression on the 1st and 4th days
in rats with colistin-induced nephrotoxicity however, the effect was not
observed on day 7. In addition, serum creatinine level did not change in
this period and it was emphasized that the KIM-1 parameter is a more
sensitive marker than creatinine 15,30. In the current
study, resatorvid treatment may have decreased the levels of IL-18, NGAL
and KIM-1 in the urine by inhibiting the TLR4 pathway, reducing
inflammation and kidney damage. This hypothesis is strengthened by the
considerable decline in inflammation and nephropathological results in
the histopathological examination. Alpha lipoic acid may have decreased
oxidative stress with its antioxidant effect and decreased KIM-1 level
by providing tissue regeneration.
It has been stated that biomarkers such as KIM-1 and NGAL released
during tubular injury can be more accurate, earlier, real-time and
proportional to injury than conventional markers 26.
The administration of GM (100 mg/kg, intraperitoneal) for 7 days,
increases statistically urinary creatinine and albumin levels, while
creatinine clearance did not change 31. Glomerular
filtration is impaired due to GM caused to damage in the proximal
tubules, and creatinine clearance decrease and increase in urine protein
levels 20,31. GM hasn’t caused to change in urine
creatinine, microalbumin, and protein levels at 30 and 100 mg/kg in rats
on day 4 however, it has increased their levels at only 100 mg/kg dose
of GM on day 8. As a result of impaired glomerular filtration, urinary
microalbumin, creatinine, and protein levels have increased and
creatinine clearance partially decreased 26.
Resatorvid inhibits inflammatory factors (IL-1β, IL-18, etc.) and the
TLR4/NF-κB/NLRP3 signaling pathway in vivo. It also inhibits apoptosis
and the TLR4/NF-κB pathway in podocytes in vitro 32.
ALA (100 mg/kg, oral) treatment decreases oxidative stress and urine
protein levels, increases antioxidant enzyme levels and creatinine
clearance, and ultimately causes regeneration of kidneys in
cisplatin-induced nephrotoxicity 13. In addition, ALA
inhibits lipid peroxidation in kidney tissue by reacting with endogenous
electrophilic molecules, free radicals and reactive drug metabolites,
due to it has nucleophilic and antioxidant properties (Murugavel and
Pari 2004). In the current research, no increase in serum creatinine
levels suggests that nephrotoxicity is in the early stage however,
microalbumin, creatinine, protein levels in the urine were statistically
increased compared to the control group in GM group. However, GM
treatment caused histopathologically moderate inflammation, tubular
damage, and necrosis as reflected in other biomarkers. It shows that
serum creatinine and urea levels do not increase in the early stages of
nephrotoxicity, but it would be more significantly to use more specific
markers such as KIM-1 and NGAL. Moreover, the results were confirmed by
histopathological results. On the other hand, resatorvid treatment may
have been suppressed inflammatory cytokines and TLR4/NF-κB/NLRP3
signaling pathway. ALA treatment may have been reduced oxidative stress
by inducing antioxidant enzymes however, this effect limited for the
regeneration of the glomerulus. Therefore, ALA treatment could be
partially prevented the increased in urinary protein and creatine
levels.
Free radicals formed inflammation, apoptosis and cytotoxicity in renal
tissues via NF-κB and p38-MAPK after GM treatment 33.
GM significantly increases the renal expression of TLR-4/p38MAPK, and
NF-κB, and induces acute kidney injury 34. NRF2
expression is induced due to oxidative stress caused by GM, and
apoptosis and acute renal failure develop by induction of caspase-3
expression 35,36. NR4A2 gene expression is increased
in order to provide cell hemostasis in pathological conditions such as
ischemia and some cancer types 37. ROS/NF-κB/NR4A2
signaling pathway is induced through increased oxidative stress,
inflammation and free radicals and apoptosis occurs38. Resatorvid suppresses NF-κB and MAP kinase/AP-1
activity and the expression of some cytokines 39. ALA,
a powerful thiol antioxidant, protects cells against oxidative stress
and apoptosis by reducing lipid peroxidation and oxidative stress,
inhibiting JNK and NF-κB signaling pathways 40. In
addition, it protects renal tubular cells against nephrotoxicity by
suppressing caspase-9 and caspase-3 41. In the current
study, resatorvid therapy may have suppressed partially oxidative
stress, free radicals and inflammation and apoptosis by inhibiting
ROS/NF-κB/NR4A2 and TLR-4, and by suppressing caspase-3 expression. It
may have ensured the survival of renal cells and minimized damage. ALA
may have not been able to reduce inflammation sufficiently because it
partially suppressed NF-kB expression. Accordingly, it may not have
enough effect on IL-18, KIM-1, and NGAL parameters, which are more
specific for nephrotoxicity. However, NRF and NR4A2 gene expressions may
have been regulated by the antioxidant effects of ALA and increasing
cellular antioxidant enzymes. Therefore, it may have reduced apoptosis
and renal damage by inhibiting caspase-3 expression.