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Gomori's Calcium Phosphate stained, 5 µm thick longitudinal section of kidney from group-A (control) rat showing regularly arranged brownish black deposits of alkaline phosphatase (ALP) within proximal tubules. Photomicrograph × 1000.
Source publication
Kidneys are adversely affected by a wide variety of therapeutic agents and chemicals including the environmental pollutants such as Lead. The nephrotoxic effects of lead have been widely studied. The proximal tubular cells are especially vulnerable to lead induced damage to membrane structure and function, characterized by enzymuria and inhibition...
Context in source publication
Context 1
... present study was designed to observe the lead induced nephrotoxicity with role of zinc in albino rats. The histochemical observations of renal Alkaline phosphatase were based on the study of sections, stained with Gomori's Calcium Phosphate method. The Gomori's Calcium Phosphate stained sections of group A rats showed the sites of enzyme activity of alkaline phosphatase in the renal proximal tubules in the form of brownish black deposits. The deposits were seen regularly and evenly arranged within the tubules (Fig. ...
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Acute kidney injury (AKI) following platinum-based chemotherapeutics is a frequently reported serious side-effect. However, there are no approved biomarkers that can properly identify proximal tubular injury while routine assessments such as serum creatinine lack sensitivity. Kidney-injury-molecule 1 (KIM-1) is showing promise in identifying cispla...
Citations
... Highest concentrations are found in the liver and mineralizing bone, but the enzyme is also present in the intestines, placenta, kidneys, and leukocytes (McComb et al. 1979;Weiss et al., 1989;Iba et al. 2004;Mota et al., 2008). Alkaline phosphatase helps in ionic movement across the cell membrane and is also associated with secretory and absorption processes of the cell ( Bansal and Roy, 1997;Khan et al., 2011). ALPase has role in bone mineralization (Van Hoof and De Broe, 1994;Hui and Tenenbaum, 1998;Mota et al., 2008). ...
Summary
Statins, such as atorvastatin (ATOR) and rosuvastatin (ROSU) are used as
cholesterol-lowering drugs. Because statins widely used, commercially available and
increasingly used day by day, with few studies and limited data existed on atorvastatin
or rosuvastatin-induced histological, histochemical and ultrastructural changes, the
present study was conducted to investigate the potential toxicity of the human
equivalent therapeutic doses of ATOR and ROSU in Wistar albino rats.
The study was conducted using apparently healthy adult male Wistar albino rats
(Rattus norvegicus) obtained from the Laboratory Animal Center (College of Pharmacy,
King Saud University, Saudi Arabia). The rats were nearly of the same age (8-10 weeks
old) and weighing (220-250 g). All animals were kept in the laboratory conditions for a
period of 7 days for acclimatization. Animals were maintained under standard
management conditions (light, temperature and humidity) and were fed with
commercial rat pellets and drinking water ad libitum. All experiments were conducted
in accordance with the guidelines approved by Local Animal Care and Use Committee
of King Saud University.
A total of 120 adult Wistar male albino rats, were divided randomly into 6
groups of 20 animals each. All doses of treated groups were human equivalent
therapeutic doses. Both drugs (ATOR and ROSU) were dissolved in 0.25% sodium
carboxymethyle cellulose (CMC). ATOR-treated rats (5mg/kg/day), ATOR-treated rats
(2.5mg/kg/day), ROSU-treated rats (2.5mg/kg/day), ROSU-treated rats
(1.25mg/kg/day), (vehicle control) was intubated with (1mg/kg/day) (CMC 0.25%) and
control rats was treated with (5mg/kg/day) physiological saline. All treatments were
administered orally (gavage) for 90 consecutive days. At the end of the experimental
period, blood samples were collected from 10 animals from each group. Relevant blood
Summary v
biochemical parameters (Alkaline phosphatase (ALP), Alanine aminotransferase (ALT),
Aspartate aminotransferase (AST), creatinine, urea, uric acid, total cholesterol and total
protein) were determined. Then animals were sacrificed and tissue samples from liver,
kidney, heart, testes, brain and lung were processed for sectioning and examination by
light and transmission electron microscope. The results of this study could be
summarized as follows:
First: Blood chemical alterations:
Administration of statins (ATOR) or (ROSU) to all treated groups caused significant
increases (P<0.05) in the levels of aspartate transaminase (AST), alanine transaminase
(ALT) and alkaline phosphatase (ALP), creatinine (Cr), urea (Ur), uric acid levels
compared with those of the control group after 90 days of exposure to statins. This
treatment also induced significant decreases in the levels of cholesterol and total
protein. The significant differences were clearly observed in high dose treated-groups
[(ATOR 5 mg/kg) and (ROSU 2.5 mg/kg)] more than low dose treated-groups [(ATOR
2.5 mg/kg) and (ROSU 1.25 mg/kg)]. In (CMC, vehicle control) the results showed
non-significant differences compared with those of the control group.
Second: Gross examination:
In terms of the anatomical appearance of organs of control animals during 90-
day study period, all therapeutic doses of atorvastatin and rosuvastatin had no effect on
gross pathological changes in all investigated organs of all members of treated groups.
Third: Histological alterations
All statin-treated groups [(ATOR 5 mg/kg), (ATOR 2.5 mg/kg), (ROSU 2.5
mg/kg) and (ROSU 1.25 mg/kg)] showed histological alterations in kidney, liver, heart,
lung, brain and testes, especially at the high doses (ATOR 5 mg/kg) and (ROSU 2.5
mg/kg). Renal alterations include the degeneration of the tissues up to the necrotic
Summary vi
patterns, as well as dilatation of blood capillaries and spacing between the renal tubules
due to accumulation of fluid (edema). However, the cortex of kidney showed more
damage especially in proximal convoluted tubules (PCT) than the medulla. The liver
showed some necrotic and hemorrhagic foci especially in (ATOR 5 mg/kg) and (ROSU
2.5 mg/kg). Hemorrhages and dilatation of the portal space and blood sinusoids of the
liver were observed. ROSU had greater effects on the hepatic tissue than ATOR. The
heart showed some sort of hemorrhages and wavy appearance of myofibers, as well as
the sarcoplasm of some fibers was characterized by granular appearance. The lung
tissue showed an increase in the thickness of alveolar walls associated with dilation or
collapsing of some pulmonary alveoli. While the testicular tissue showed degenerative
changes in some seminiferous tubules leading to partial arrest of spermatogenesis, as
well as some necrotic cells and spermatid giant cells were shown in some seminiferous
tubules of high dose groups. Moreover, The brain of statins-treated rats showed little
changes characterized by slight dilatation of blood capillaries with little edema around
the neurons in cerebral cortex. No histological changes were observed in (CMC, vehicle
control).
Fourth: Histochemical alterations
Exposure to statins (ATOR) or (ROSU) caused alterations in content of
chemical substances of different rat tissues. All treated groups, especially high doses
(ATOR 5 mg/kg) and (ROSU 2.5 mg/kg) manifested less content of proteins in the renal
and hepatic tissues compared with control group. Liver tissues in (ATOR 5 mg/kg) and
(ROSU 2.5 mg/kg) showed reduction in glycogen content, as well as accumulation of
glycogen in subsarcolemma of heart tissue of treated rats. Liver tissue in (ATOR 5
mg/kg) and (ROSU 2.5 mg/kg) showed reduction of neutral lipid droplets compared
with control group. The kidney tubules in all treated groups showed an obvious
Summary vii
increased activity of alkaline phosphatase (ALPase). The liver tissue and kidney tubules
in all treated groups showed clear increased activity of glucose-6- phosphatase
(G6Pase). In comparison with the liver of control group, apoptotic cells were observed
in some hepatocytes of ATOR and ROSU-treated groups. Cytoplasmic inclusions with
eosinophilia were observed as hyaline droplets in the cytoplasm of some proximal
convoluted tubule (PCT) cells of ATOR and ROSU-treated rats. No histochemical
changes were observed in (CMC, vehicle control).
Fifth: Ultrastructural alterations
The epithelial cells lining the PCT of most statin-treated groups, especially in
(ATOR 5 mg/kg) and (ROSU 2.5 mg/kg) showed ultrastructural changes such as
cytoplasmic vacuolization, swollen mitochondria with clear destroyed cristae beside
presence of large dense bodies inside some of swollen mitochondria. The glomeruli
showed damaged endothelial cells of blood capillary and dilation of some glomerular
blood capillaries. These changes were clear in most treated groups except G4 in which
their kidneys were almost normal.
The ultrastructure of hepatocytes of treated groups showed accumulation of
lipid droplets and glycogen in cytoplasm of affected hepatocytes. Most hepatocytes
nuclei showed irregular shape, swelling of mitochondria and destruction of their cristae.
The cardiac muscle of (ATOR 5 mg/kg) and (ROSU 2.5 mg/kg), showed
ultrastructural changes in their muscle fibers with clear rupture of some muscle fibers
and separation of the fibers from each other together with mitochondria swelling and
cristae destruction. Discontinuous of elongation of cardiac muscle fiber was observed
which might be due to occurrence of partial decomposition in muscle fibers of some
animals. Ultrastructural of cardiac muscle fiber exhibited almost normal structure
Summary viii
without any changes in muscle fibers and mitochondria in low dose (ATOR 2.5 mg/kg)
and (ROSU 1.25 mg/kg).
The ultrastructure of skeletal muscle of (ATOR 5 mg/kg) and (ROSU 2.5
mg/kg), showed ruptured muscle fibers and spacing from each other, also showing
discontinuous of elongation of muscle fiber and swelling of the mitochondria and
destruction of their cristae. The ultrastructure of skeletal muscle fibers of low dose
groups (ATOR 2.5 mg/kg) and (ROSU 1.25 mg/kg) was almost normal without any
changes in muscle fibers and mitochondria. No ultrastructural changes were observed in
(CMC, vehicle control).
From the above findings, it could be concluded that the therapeutic doses of
(ATOR or ROSU), especially high doses, induced considerable histological,
histochemical and ultrastructural alterations in different vital organs which might alter
their functions. Further studies are recommended to be carried out to corroborate these
findings.
