Abstract
Objectives
Diabetes mellitus (DM) contributes to the development and progression of nephropathy and kidney diseases. Statins are known to have anti-inflammatory and antifibrotic effects. We aimed to test the short-term effect of atorvastatin on renal biomarkers of oxidative damage, inflammation, and fibrosis in a rat model of streptozotocin-induced DM.
Methods
Wistar rats were divided into; control rats, rats treated with atorvastatin (Ator, oral 40 mg/kg for 6 weeks), DM rats (DM, one intraperitoneal 40 mg/kg streptozotocin), and atorvastatin-treated DM rats (DM + Ator). Renal oxidative stress markers, inflammatory and mitogenic factors were measured.
Results
Streptozotocin induced an increase in serum glucose, blood urea nitrogen, and creatinine levels. A marked increase in kidney to body weight ratio was found in DM groups. Diabetes resulted in an elevation in inflammatory biomarkers of galectin-3 and endothelin-1. Hyperglycemia induced an increase in lipid peroxides and a decrease in the superoxide dismutase (SOD) antioxidant level in the DM group. A significant increase in the fibrotic factor platelet derived factor-BB (PDGF-BB) expression was documented in the DM group. Six weeks use of atorvastatin normalized kidney endothelin-1, galectin-3, and the PDGF-BB, and attenuated the increase in lipid peroxides and the reduction in SOD levels.
Conclusion
Our findings suggest that short-term use of atorvastatin may attenuate the substrates for diabetic nephropathy via partial decrease of renal markers of inflammation, oxidative stress, and fibrosis.
Keywords: Diabetes, Kidney disease, Atorvastatin, Inflammation, Oxidative stress, Fibrosis
Introduction
Diabetes Mellitus (DM) promotes the development of cardiovascular disease and diabetic nephropathy and chronic kidney [1]. Current therapeutic interventions of diabetic nephropathy focus on the prevention of kidney damage and underlying comorbidities by the control of hyperglycemia and associated risk factors. Chronic kidney disease (CKD) contributes to hyperlipidemia, which in return is linked to development and progression of diabetic kidney disease [2].
Current research has focused on the therapeutic potential of statins as an intervention to reduce blood cholesterol and prevent cardiovascular diseases [3]. Strong evidence suggests that statins have pleotropic effects including anti-inflammatory, anti-oxidant and anti-fibrotic probertites. Statins prohibit the development of myocardial remodeling and decrease inflammatory and fibrotic cytokines, and glucose intolerance in diabetic cardiomyopathy [4]. However, the impact of statins on diabetic nephropathy remains relatively unclear and controversial [5].
Oxidative stress is an essential mediator of various pathological conditions including diabetic nephropathy [6]. It has been found that hyperglycemia induced renal oxidative damage as indicated by the marked reduction in the activities of kidney catalase, superoxide dismutase (SOD), malondialdehyde, and reduced glutathione level [7]. Accelerated matrix deposition is observed in diabetic kidney disease and even in the early stages of microalbuminuria [8]. Endothelin-1 (ET-1) is an inflammatory protein that has been implicated in diabetic nephropathy [9]. Galactin-3, an inflammatory factor, has been implicated in kidney fibrosis. Circulating galectin-3 is an important predictor for diabetic nephropathy progression in DM patients [10]. The effect of statins on renal ET-1 and galectin 3 expression is not known. The aims of this study are to evaluate the impact of atorvastatin on kidney biomarkers of oxidative stress, inflammation, and fibrosis in a rat model of DM.
Methods
Animals
Wistar rats (weight of 250–300 g) were housed in cages at room temperature with 12-hour dark/light photoperiods and received free amounts of food and water. The study was approved by the Animal Care and Use Committee (ACUC) at Jordan University of Science and Technology (approval number 16/4/12/455, Date 9/9/2021).
Design of the study
Rats (12–15 rats each group) were randomly distributed into four groups:
(1) control rats without diabetes (CTR): rats received one dose of intraperitoneal citrate buffer (10 mmol/L) and daily dimethyl sulfoxide (DMSO) by oral gavage.
(2) Atorvastatin treated rats without diabetes (Ator): rats received one dose of intraperitoneal citrate buffer (10 mmol/L) and a daily atorvastatin (40 mg/kg body weight) dissolved in DMSO by oral gavage.
(3) Diabetes rats (DM): rats received one intraperitoneal streptozotocin injection (40 mg/kg) dissolved in citrate buffer (10 mmol/L) and daily DMSO by oral gavage.
(4) Diabetes rats treated with atorvastatin (DM + Ator): rats received one intraperitoneal streptozotocin injection (40 mg/kg) dissolved in citrate buffer (10 mmol/L) and daily atorvastatin (40 mg/kg body weight) dissolved in DMSO by oral gavage.
After streptozotocin injection, rats were maintained for 24 h on sucrose solution (10%) dissolved in the drinking water to prevent occurrence of hypoglycemia.
Diabetes was confirmed when glucose levels were equal 300 mg/dl or higher after a week of streptozotocin injection, and by the development of polydipsia and polyuria. Measurement of blood glucose level were performed using the tail-prick glucometer method (Accu-Chek Performa, Roche Diagnostic GmbH, Mannheim, Germany).
Atorvastatin was given for 6 weeks after the confirmation of diabetes (about a week after streptozotocin injection). This dose was found to have a significant reduction in lipid levels [11].
The duration of the study was preplanned to be eight weeks based on a pilot study to determine humane end points which include behavioral changes such as inactivity of rats, inability to access food or water, rapid weight loss, dehydration, and changes in physical appearance. Animals were observed frequently daily by well-trained personnel. Since some animals reached humane end points at six weeks, all animals were killed prematurely after six weeks of treatment to study the effect of atorvastatin over a fixed period for all animals without confounding of time duration.
Blood collection
At the last day of the study, animals were killed by decapitation and fresh trunk blood was collected and centrifuged at 2500 rpm for 10 min to collect serum samples. Concentrations of serum urea, blood urea nitrogen (BUN) and creatinine were assessed using standard colorimetric kits (Urea assay kit, BioSystems S.A. Costa Brava, Barcelona, Spain & Creatinine assay kit, SPINREACT, S.A.U., Ctra.Santa Coloma, Spain).
Molecular analysis of kidney biomarkers
After decapitation, the left kidney was immediately removed, weighed, and kept at -80ºC freezer. At time of analysis, the kidney was homogenized in a mixture of cold phosphate buffer saline (PBS) and cocktail of protease inhibitors. Homogenized kidneys were centrifuged at 14500x rpm at 4 °C for 15 min and the extracted supernatant was used to measure kidney biomarkers. Samples were kept in the freezer at -80 °C until molecular analysis.
Kidney levels of thiobarbituric acid reactive substances (TBARS) were measured using TBARS assay kit (R&D Systems, MA, USA). Total nitrite levels were measured using the nitric acid parameter assay kit (R&D Systems, MA, USA). The protein level of superoxide dismutase (SOD) was determined using colorimetric assay (Sigma-Aldrich Corp, St. Louis, MO, USA). Concentrations of kidney myeloperoxidase (MPO), glutathione peroxidase and galectin-3 were tested by specific ELISA kits (Rat MPO, Gpx and Gal-3 ELISA kits, MyBioSource, Inc. CA, USA). Kidney contents of endothelin-1 (ET-1), platelet derived growth factor-BB, and transforming growth factor-beta 1 (TGF-β1) were measured by ELISA kits (Quantikine ELISA, R&D Systems, MA, USA).
Epoch Biotek microplate reader (BioTek, Winooski, VT, USA) was used to measure the absorbance of the 96-well plates at the specified wave-length for each kit. All tissue assays were standardized based on total protein concentrations.
Statistical analysis
Data are expressed as means ± SEM (standard error of the mean). The Shapiro-Wilk test was used to test data normality. Normally distributed data were analyzed using analysis of variance (ANOVA) followed by Tukey test. Non-normally distributed data were compared using Kruskal-Wallis tests followed by the Dunn’s post hoc tests.
A probability value (p) below 0.05 was set statistically significant.
GraphPad Prism 9 (GraphPadSoftwareInc.,LaJolla, California, USA) was used to conduct statistical analysis.
Results
Serum levels of glucose, urea, and creatinine
An increase in serum glucose concentration of more than 3.5-folds was observed at the end of the study in the DM and the DM + Ator groups without differences between the groups (p < 0.0001, Fig. 1.A).
Fig. 1.
Serum glucose, urea, BUN, and creatinine levels. Serum glucose at the end of the study (A), urea (B), blood urea nitrogen (BUN, C), and creatinine levels (D) for control rats (CTR, n = 13), rats treated with atorvastatin (Ator, n = 14), DM rats (n = 10), and atorvastatin-treated DM rats (DM + Ator, n = 12). *p < 0.05, **p < 0.001, ***p < 0.0001 vs. control. Error bars represent mean ± SEM
Serum urea and blood urea nitrogen levels were increased by 1.5-folds in the DM and the DM + Ator groups with no differences between them (Fig. 1. B-C, p = 0.0003). Serum creatinine level was also increased by two folds in the DM and the DM + Ator groups and use of atorvastatin did not change its level as compared to control (Fig. 1. D).
Changes in kidney to body weight ratio
After 6 weeks, the body weight (BWT) was markedly decreased in the DM and DM + Ator groups without a notable difference between them (BWT = 318.1 ± 7.6, 330 ± 6.8, 247.5 ± 11.1, 252.5 ± 6.3 g for control, atorvastatin, DM, and atorvastatin treated DM rats, p < 0.0001). A trend of an increase in the left kidney weight (KWT) was observed in the DM and DM + Ator groups, and when adjusted to BWT, the increase was statistically significant (KWT/BWT = 3.25 ± 0.11, 3.38 ± 0.05, 5.07 ± 0.25, and 5.04 ± 0.12 mg/g for control, atorvastatin, DM and atorvastatin treated DM rats, p < 0.0001).
Effect of atorvastatin on kidney markers of oxidative stress
A trend of an increase in kidney TBARS substances was observed in the DM group and the use of atorvastatin prevented this increase in the DM + Ator group (p = 0.042, Fig. 2. A). No differences were found for total nitrite levels (p = 0.55, Fig. 2. B). Relative to control, the level of SOD protein was reduced in the DM group and was not changed in the DM + Ator group (Fig. 2. C). Level of Gpx enzyme was higher in the DM + Ator group relative to the atorvastatin treated group (p = 0.008, Fig. 2. D).
Fig. 2.
Impact of atorvastatin on renal oxidative stress. Renal thiobarbituric substances (TBARS) levels (A), total nitrite (B), superoxide dismutase (SOD, C), and glutathione peroxidase (Gpx, D) in the control rats (CTR, n = 13), rats treated with atorvastatin (Ator, n = 14), DM rats (n = 10), and atorvastatin-treated DM rats (DM + Ator, n = 12). *p < 0.05 vs. CTR, $p < 0.05 vs. atorvastatin group. Error bars represent mean ± SEM
Effect of atorvastatin on kidney markers of inflammation
Kidney ET-1 levels were lower in the atorvastatin and the DM + Ator group relative to the DM group (Fig. 3. A, p = 0.019). Kidney MPO protein was not different among study groups (p = 0.26, Fig. 3. B); however, galectin-3 levels were markedly elevated in the DM group, p = 0.0173. Levels of kidney galectin-3 in the DM + Ator group were similar to controls (Fig. 3. C).
Fig. 3.
Impact of atorvastatin on renal inflammatory markers. Renal endothelin-1 (ET-1) levels (A), myeloperoxidase (MPO, B), and galectin-3 (C) in the control rats (CTR, n = 13), rats treated with atorvastatin (Ator, n = 14), DM rats (n = 10), and atorvastatin-treated DM rats (DM + Ator, n = 12). *p < 0.05 vs. CTR, #p < 0.05 vs. DM group. Error bars represent mean ± SEM
Effect of atorvastatin on kidney markers of fibrosis
Compared to control, a trend of elevated kidney TGF-β1 protein was found in the DM group, but the difference was marginally significant (p = 0.055, Fig. 4. A).
Fig. 4.
Impact of atorvastatin on renal fibrotic markers. Renal transforming growth factor- beta (TGF-β) levels (A), and the platelet derived growth factor-BB (PDGF-BB, B) in the control rats (CTR, n = 12), rats treated with atorvastatin (Ator, n = 13), DM rats (n = 10), and atorvastatin-treated DM rats (DM + Ator, n = 11)). #p < 0.05 vs. DM group
On the other hand, protein level of PDGF-BB in the kidney was markedly elevated in the DM group, and its level was lower in the atorvastatin treated group as compared to the DM group (p = 0.008, Fig. 4. B).
Discussion
Diabetic kidney disease is a common complication of DM and accounts for 50% of CKD and end stage renal disease [1]. Statins arguably show renal protective effects in the general population and cardiovascular protective effects in CKD patients who do not need dialysis. Statins can also be used as adjunctive therapy to prevent contrast induced nephropathy and cardiorenal syndrome in a dose dependent manner [12]. The effect of statin may be affected by the duration, the dose, and the nature of underlying disease or pathology [12]. Currently, there is insufficient evidence to support routine use of statins for kidney protection. We were interested in evaluating the short effect of statins on diabetic nephropathy and renal substrates, as chronic use has been suggested to exacerbate diabetic nephropathy [5].
Our study indicated that the use of streptozotocin induced signs of nephropathy as indicated by the increase in urea, BUN, and creatinine levels in DM rats. However, six-weeks use of atorvastatin did not attenuate these changes. This could be due to the limited duration of the study or the use of different doses and routes of administration. On the other hand, statins may exert a differential impact based on the duration of treatment as it was found that long term administration of atorvastatin for 50 weeks in streptozotocin rats exacerbates diabetic nephropathy [5]. Interestingly, long-term statin use was associated with an increased incidence of acute and chronic renal disease in retrospective cohort study [13]. Future studies should compare the short and the long-term impact of statins on risk of kidney disease.
Oxidative stress is a key mediator of diabetic kidney disease. In streptozotocin-induced DM model, oxidant biomarkers are increased while antioxidants are decreased [14]. Advanced glycation end-products (AGEs) promote oxidative stress leading to diabetic nephropathy. Atorvastatin reduced the expression of advanced glycation end-products and receptors [15]. Interestingly, atorvastatin increased renal activities of SOD and glutathione content but reduced the malonaldehyde levels [16]. In diabetic mice [17], atorvastatin treatment reduced renal injury, ROS generation, mitochondrial damage, and renal expression of malondialdehyde while increasing renal levels of GPx. In our study, levels of TBARS, which are lipid peroxides, were increased in the DM group but not in the atorvastatin treated streptozotocin rats. In addition, the SOD antioxidant protein was reduced in the streptozotocin rats, and the use of atorvastatin normalized its level as in control. In a similar study, rosuvastatin treatment of diabetic rats also normalized the antioxidant status similar to control values [7]. Interestingly, the level of GPx protein, an antioxidant, tended to increase in the DM groups which could be a compensatory mechanism to prevent the acute damage that could occur because of increased free radicals/lipid peroxides in STZ rats. However, six weeks of atorvastatin did not show any notable effect. Together, these findings indicate that treatment with atorvastatin attenuates renal oxidative damage by improving antioxidant enzymes levels and reducing ROS generation.
Endothelin-1 is a powerful vasoconstrictor, inflammatory and fibrotic molecule [3]. Interestingly, we found that ET-1 local production in the DM kidneys was markedly increased, and the use of atorvastatin significantly prevented this increase.
MPO is a catalyst for lipoprotein oxidation and cellular dysfunction of the kidneys. MPO catalyzes the production of reactive oxygen and nitrogen intermediates and free radicals. The oxidants produced by MPO serve as microbicidal agents and are crucial for the innate immune response [18]. However, MPO-derived oxidants can also promote oxidative damage to biomolecules leading to tissue damage [18]. This oxidative damage may contribute to endothelial dysfunction and the development cardiovascular and other complications in patients with CKD [18]. Following ischemia/reperfusion, MPO activity is elevated in the injured kidney as a result of relocation of neutrophils to the site of injury [18]. MPO levels along with other inflamatorry mediators are elevated in patients with diabetic nephropathy compared to healthy individuals [19]. In our study, a wide variation was found in the MPO protein level with a trend of elevation in the DM group. In addition, no significant changes in total nitrite production were found. Future larger animal and human studies would provide better understanding of the significance of MPO in diabetic nephropathy.
Recent research has identified galectin-3 as an important player of many pathological processes, such as inflammation, immunity, fibrosis, and tumorigenesis [10]. In a large study including diabetic patients undergoing dialysis, galectin-3 predicted long-term outcomes, MI, cardiovascular mortality, and sudden cardiac death [20]. In this study, hyperglycemia induced an increase in galectin 3 protein expression in the kidney and the use of atorvastatin normalized its level as in control rats, highlighting the anti-inflammatory effects of statins.
Kidney fibrosis is a key metabolic irreversible change in the late stage of diabetic kidney disease [21]. The TGF-β1 promotes proliferation of kidney fibroblasts by inducing myofibroblasts generation [22]. In streptozotocin treated rats, renal TGF-β1 mRNA was upregulated and treatment with atorvastatin therapy for 8 weeks reduced renal TGF-β1 mRNA expression [23]. The level of platelet derived growth factor (PDGF-BB), another key fibrotic factor, is elevated in renal tissue of diabetic rats [24], however, the effect of statins on renal PDGF-BB expression is not clear. In the present study, although a trend of increase in TGF-β1 protein was found in the DM group, the p value was marginally significant, but the TGF- β1 level in the atorvastatin treated diabetic rats was similar to control. On the other hand, a significant increase in the protein expression of the PDGF-BB was found and the use of atorvastatin normalized its expression, indicating that statins can prevent the significant production of profibrotic molecules. Increased kidney to body weight ratio is an indicator of development of structural changes and it was elevated in DM treated rats regardless of statin treatment. This suggests that DM promotes kidney remodeling and six weeks treatment with atorvastatin was not sufficient to prevent this change.
Based on our findings and those of other studies, atorvastatin should be considered for diabetic patients who show early signs of nephropathy, especially those with elevated oxidative stress, inflammation, and fibrosis markers, as well as those at high risk for cardiovascular events. However, patients on high-dose or long-term statin therapy, those with advanced renal disease, or those who have previously experienced side effects from statins should be closely and regularly monitored for any signs of worsening nephropathy. While atorvastatin may provide protective benefits [25], its use should be personalized, taking potential side effects into account. Continuous research and careful clinical judgment are crucial to achieving the best outcomes.
Conclusions
Our study suggests that DM promoted nephropathy and an increase in the kidney to body weight ratio coupled with an increase in inflammatory, oxidant and profibrotic factors. Although atorvastatin prevented the increase in some inflammatory, oxidant and profibrotic markers, it did not prevent diabetic nephropathy. This could be due to the short duration of the study. Further short and longer duration studies testing a wider range of biomarkers are required to understand the impact of statins on diabetic nephropathy. In addition, it’s important to interpret results from animal studies cautiously, as the treatment doses used may not directly translate to human doses.
Acknowledgements
None.
Funding
This study was funded by the deanship of research (grant number 184/2023) at Jordan University of Science and Technology, Irbid, Jordan.
Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Declarations
Ethical approval
The study was approved by the Animal Care and Use Committee (ACUC) at Jordan University of Science and Technology (approval number 16/4/12/455, Date 9/9/2021).
Conflict of interest
The authors declared that they have no conflict of interest.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.