Trinitroglycerine-loaded Chitosan Nanoparticles Attenuate Renal Ischemia- Reperfusion Injury by Modulating Oxidative Stress

doi:10.21203/rs.3.rs-4852600/v1

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Trinitroglycerine-loaded Chitosan Nanoparticles Attenuate Renal Ischemia- Reperfusion Injury by Modulating Oxidative Stress

https://doi.org/10.21203/rs.3.rs-4852600/v1

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Background: Renal ischemia-reperfusion (I/R) injury is a common clinical factor for acute kidney injury (AKI). A current study investigated the renoprotective effects of the trinitroglycerine (TNG) combination with chitosan nanoparticles (CNPs) on renal I/R-induced AKI.

Methods: Rats were randomly assigned to five groups (n=8/group): Sham, I/R, TNG (50 mg/kg) + I/R, CNPs (60 mg/kg) + I/R, and TNG-CNPs + I/R. Bilateral renal pedicles were occluded for 60 minutes to induce ischemia. TNG, CNPs, or TNG-CNPs were administered intraperitoneally 30 minutes before renal ischemia. After 24 hours of reperfusion, blood samples were collected, and both kidneys were removed. The left kidney was used for oxidative stress analysis. The right kidney was preserved in 10% formalin for histopathological examination via H&E staining.

Result: After renal I/R injury, plasma creatinine (Cr), blood urea nitrogen (BUN), and glomerular filtration rate (GFR) significantly increased in rats. Total oxidative stress (TOS) levels were also significantly higher in the I/R group, whereas total antioxidative capacity (TAC) was reduced. Histopathological examination revealed damage in the kidneys of rats in the I/R group. Pretreatment with the TNG-CNP formulation before I/R increased plasma and tissue TAC levels in rats. It also corrected the renal histopathological changes and functional disorders induced by I/R injury, as evidenced by reduced Cr and BUN, increased GFR, and attenuated oxidative stress.

Conclusion: The results suggest that the TNG-CNP combination provides renoprotective effects against I/R-induced AKI by improving antioxidant status and minimizing renal injury.

Biological sciences/Biological techniques

Biological sciences/Biotechnology

Biological sciences/Drug discovery

Physical sciences/Nanoscience and technology

Nanoparticle

Chitosan

Trinitroglycerine

Renal ischemia-reperfusion

Oxidative stress

Renoprotective

Acute kidney injury (AKI) induced by renal ischemia/reperfusion (I/R) injury is an emergency and severe clinical disorder with high morbidity and mortality (1). Renal ischemia has a complex pathophysiology (2). Ischemia triggers kidney injury, impairing the oxygen and nutrient supply to tubular cells and their ability to excrete waste products. Although reperfusion restores blood flow, it can paradoxically promote glomerular, vascular, and tubular disturbances. Renal I/R stimulates the excessive production of reactive oxygen species (ROS) and inflammatory cytokines, leading to structural and functional dysfunction (3, 4).

AKI induced by renal I/R is a severe clinical problem without specific medicine now except for expensive hemodialysis treatment (5). Kidney-targeted drugs are not more, and small molecules are excreted too rapidly to reach effective drug concentrations in damaged kidneys (6, 7). Based on these problems, the management of AKI is still limited in scope today. Nanotherapeutics based on nanotechnology aim to design and prepare nanoparticles (NPS) from the molecular and atomic scale to bulk form, which may solve the pharmacological therapy problem (8-10).

More and more nanoparticle-based drugs with various physical and chemical properties are being developed to effectively distribute drugs, increase accumulation, and regulate the release of drugs in injured kidneys (11, 12). The medications based on chitosan NPS (CNPs) are tested for their ability to selectively scavenge excess ROS and prevent oxidative damage while leaving normal ROS levels intact (13, 14). This targeted antioxidant approach could lead to new nanomedicine therapies for AKI involving oxidative imbalances (15).

Trinitroglycerin (TNG), also named glycerol trinitrate, is a vasodilator mainly administrated for angina pectoris in patients suffering from chest pain and high blood pressure, which acts through the release of nitric oxide (NO) (16). Several studies have demonstrated the effects of TNG on renal injury after heart failure (17). In comparison, a limited number of studies have reported protective effects of TNG against ischemia/reperfusion injuries (18). Based on this background, this study aimed to evaluate whether the TNG-CNPs formulation provides better protection against renal I/R damage than TNG alone.

Preparation of CNPs and TNG-CNPs

CNPs are prepared using an ionic gelation method with sodium triphosphate (TPP, CAS-No 15091-98-2) as the polyanion. First, a uniform and homogeneous chitosan (low molecular weight, CAS-No 9012-76-4) solution is made by dissolving chitosan in 1% acetic acid solution at a weight-to-volume concentration of 0.06. The TPP solution is prepared by dissolving TPP in distilled water. The pH of the TPP solution is adjusted to 4 using hydrochloric acid. The TPP solution is then added dropwise to the chitosan solution under magnetic stirring at 1500 rpm and 28°C. The mixture is stirred for 2 minutes to allow NPS formation via ionic crosslinking between the chitosan and TPP. The CNP suspension is then centrifuged at 12,000g for 15 minutes. The supernatant is discarded, and the CNP pellet is resuspended in deionized water. Finally, the optimized amount of TNG drug is added to 10 ml of the 2.5% CNP solution. This mixture is magnetically stirred at 1000 rpm for 20 minutes to ensure the TNG (CAS-No 55-63-0) is well loaded within the CNP structure.

Physicochemical Characterization of CNPs and TNG-CNPs

Fourier-transform infrared spectroscopy (FT-IR) (PerkinElmer, Spectrum RXI) is used to confirm the fabrication of the CNPs and TNG-CNPs. The dried samples are mixed with potassium bromide (KBr) powder and compressed to form a tablet. This tablet is then placed in the FT-IR machine and analyzed. Transmission electron microscopy (TEM) (ZIESS, model EM10C, Germany) is employed to evaluate the size and morphology of the samples. For this, 20 microliters of the sample solution are placed on a 300-mesh copper grid (EMS) for 2 minutes. The excess liquid is removed using filter paper. Then, the sample is placed in contact with 20 microliters of 2% uranyl acetate solution for one minute. After drying, the sample is placed in the TEM for imaging and analysis. Dynamic light scattering using a Zetasizer instrument (SZ-100, Japanese) is also used to analyze the samples. This technique provides the size distribution, average hydrodynamic diameter, and polydispersity index (PDI) of the CNPs and TNG-CNPs in solution.

Animal study and ethics

In the current study, 40 adult Sprague–Dawley rats (7–8 weeks of age; average body mass 220- 250g) were obtained from the Center of Experimental and Comparative Medicine at Shiraz University of Medical Sciences, Shiraz, Iran. The rats were maintained under standard situations (a 12 h light/12 h dark cycle and at a temperature of 23–25 ºC) at the Nephro-Urology animal lab and allowed free food and water intake ad libitum until the procedures started. All animal care and experimental protocols were approved by the ethics committee of Shiraz University of Medical Sciences (Ethics code: IR.SUMS.AEC.1401.018) with an approval date of 2022/06/01. We confirmed that all methods were carried out under relevant guidelines and regulations. Moreover, we confirmed that all methods are reported following ARRIVE guidelines (https://arriveguidelines.org).

Surgical Preparation

The rat model of renal (I/R) injury was persuaded according to the procedure explained previously (R). Briefly, rats were anesthetized by intraperitoneal injection of Ketamine (100 mg/kg; Woerden, Netherlands) and xylazine (5 mg/kg; Alfazyne, Woerden, Netherlands) cocktail and kept on a heating table to sustained body temperature at 37°C through surgery. After shaving off the surgical zone, an abdominal midline incision was made, and the left and right kidney was exposed. Both renal pedicles were impeded by a microaneurysm vascular clip for 60 minutes. After the end of the ischemia period, the clamps were taken and confirmed for suitable reperfusion of the blood flow to the ischemic kidney. 3/0 stitches, then sutured the abdominal incision in 2 layers.

Experimental Design

Fourthly rats were randomized into five groups (n=8/group): Sham group, I/R group, TNG (50 mg/kg)+I/R, CNPs(60 mg/kg)+I/R, and TNG-CNPs+I/R groups. TNG and CNPs intraperitoneally were injected 30 minutes before renal ischemia. After recovery from surgery, the rats were immediately located in metabolic cages to collect the 24-hour urine sample. 24 h after reperfusion, the rats were anesthetized and sacrificed by taking blood samples from the cardiac cavity. Both kidneys were exposed and removed by mid-line abdominal incision. The left kidney was saved for oxidative stress analysis, and the right kidney was kept in 10% formalin for H&E staining.

Renal Function Assay

Blood urea nitrogen (BUN) levels and plasma and urine creatinine (Cr) concentrations were measured to evaluate renal function. BUN and Cr plasma levels were analyzed using a colorimetric assay based on the manufacturer's procedures (RA-1000 Technicon, USA). This formula, (µl/mi-1/Kg.Bw-1) = ([urine creatinine] * [urine volume rate])/plasma creatinine, was used for the calculation of glomerular filtration rate (GFR).

Oxidative Stress Assay

Whole kidney tissue (150 mg) was weighted and mechanically homogenized with potassium phosphate buffer (Ph=7.35). Tissue suspension was centrifuged at 10,000×g for 10 min at four °C, and the supernatants were separated and saved for oxidative stress assay. Total antioxidative capacity (TAC) and total oxidative stress (TOS) were assessed by a commercial kit (KTOS96 & KTAC96, KiaZist, Hamedan, Iran) through a microplate reader (Epoch 2 TM,

BioTek, Santa Clara, USA) at 490 and 560 nm wavelengths. Moreover, the oxidative stress index (OSI) was calculated as a ratio of TOS level to TAC level by the following formula:

OSI (arbitrary unit) = TOS (nmol H2O2 Equiv./mg of protein) / TAC (nmol Trolox Equiv./mg of protein) × 100

Histopathological Assay

The right kidney was fixed in 10% buffered formalin and embedded in paraffin. The kidney's histological sections (5 µm‑thick) were used for hematoxine and eosin staining (H&E). Tubular degeneration, Bowman’s space enlargement, vascular congestion, and intratubular cast were evaluated in the cortex and medulla area in the kidney. The amount of structural damage was scored based on calculated percentages as follows: no damage: grade 0, 10-20 % damage: grade 1, 21-40 % damage: grade 2, 41-60 % damage: grade 3, and 61-80 % damage: grade 4, and 81-100% damage: grade 5(19).

Statistical Analysis

All data were shown as the mean ± standard error of the mean (SEM). Comparisons between the experimental groups were made using one-way analysis of variance (ANOVA) by GraphPad Prism software (Version 9.0, La Jolla, CA, USA). Tukey's post-test was also used, and P < 0.05 was considered statistically significant.

Characterization of CNPs and TNG-CNPs

The mean hydrodynamic diameter of CNPs and TNG-CNPs were 110.15 and 132.7 with a PDI⁓0.7 and 0.74, respectively. The Zeta potential of CNPs and TNG-CNPs were shown a surface charge (-1.3 mV) and (-1.47 mV), too.

The morphological evaluation of CNPs and TNG-CNPs with TEM confirmed the spherical, dense, uniform distributions (Figure 1. B and C). In addition, the mean diameters of CNPs and TNG-CNPs were 56.15±9 nm and 68.92±19 nm, respectively. The histogram of the CNPs is presented in Figure1.D and E.

The characteristic absorption bands of CNPs and TNG-CNPs were evaluated (Figure 1. A). The spectra of CNPs showed the absorbance bands at 764 cm^-1 associated with N–H and C–O, at 3420 cm^-1 referred to the stretching vibration of OH and NH. Furthermore, the peaks at 1082 cm^-1 belonged to the stretching vibration of the C-O-C, 1587 cm^-1 related to the amine group (-NH2), the bands presented at 892 cm^-1, and 1214 cm^-1 stretching vibration of P=O and P-O-P; 1151 cm^-1. TNG-CNPs, the bands at 1554 cm^-1, and 1458 cm^-1 are related to the asymmetric stretching vibration of NO₂, and peaks at 1165 cm^-1and 1127 cm^-1are associated with the symmetric stretching vibration of NO.

Change in renal function

Renal I/R injury had significantly increased plasma Cr and BUN levels compared with the sham group (P < .0001 for both BUN and Cr factors). Pretreatment of the rats with TNG resulted in significantly lower plasma Cr levels than those with rats of renal I/R (P<0.01). Interestingly, administration of TNG-CNPs severely decreased plasma Cr levels compared with the I/R group(P<0.0001). CNPs alone could not improve renal function, and plasma Cr level was significantly higher than in the CNPs+I/R group versus the sham group(P<0.01). Moreover, administration of TNG-CNPS significantly reduced BUN levels compared with the I/R group(P<0.001). However, there were no significant differences in BUN levels among the TNG+I/R and CNPs+I/R groups when compared with the I/R group (Figure. 2A and B).

Glomerular filtration rate (GFR) and urine flow rate are other renal functional indices. The urine flow rate slightly raised in the I/R group versus the sham group but remained unchanged in the three treatment groups. GFR was markedly decreased after 24h of reperfusion in the I/R group and three treatment groups compared with the sham group (all of comparison P<0.0001). However, the reduction in GFR following renal I/R injury slightly compensated and increased in the TNG-CNPs+I/R compared with the CNPs+I/R group(p<0.05) (Figure2. 1D and C).

Oxidant and antioxidant status assay

Renal I/R significantly increased TOS and OSI levels in renal tissue, an oxidative stress index, compared to a sham group (p<0.05 and p<0.01, respectively). On the other hand, rats treated with TNG, CNPs, and TNG-CNPs before renal I/R demonstrated a statistically significant reduction in TOS and OSI levels when compared with I/R or sham groups. At the same time, the oxidative stress index decreased in the TNG-CNPs+ I/R group more than in the TNG+I/R and CNPS+I/R groups(Figure. 3B and C). In contrast, the TAC level was not changed after renal I/R. However, TAC activity was higher in the treatment groups compared with the I/R (p<0.05 CNPs+I/R versus I/R and p<0.001 TNG-CNPs+ I/R versus I/R groups) and sham groups( p<0.01 TNG-CNPs+ I/R) (Figure. 3A).

Histopathological analysis

The renal tissues in the sham group demonstrated a normal appearance without structural changes (Figure. 4A and F). However, bilateral renal ischemia following reperfusion-induced pathological alterations has been seen in the cortex and medulla area (Figure. 4B and G). The highest score of damages, such as tubular degeneration, Bowman’s space enlargement, vascular congestion, intratubular cast, and total histopathological score, were exhibited in the I/R group (table 1). In the CNPs+I/R and TNG+I/R groups, increased pathological variables were not significantly diﬀerent compared to the I/R group (Figure. 4C and H, D and I, Table). Interestingly, rats pretreated with TNG-CNP significantly improved the kidney tissue when compared with I/R, TNG+I/R, and CNPs+I/R groups; however, the renal injury was still visible in the TNG-CNPs+I/R group (Figure. 4E and J, table1)

Table 1: The effect of trinitroglycerin chitosan nanoparticles (TNG-CNPs) on histopathologic alterations in the c of the renal tissue after ischemic reperfusion injury.

Variables Groups	Bowman’s Space Enlargement	Tubular Degeneration	Vascular Congestion	Intra Tubular Cast	Total Histopathologic Score
sham	0.0±0.00	0.0±0.00	0.0±0.00	0.0±0.00	0.0±0.00
I/R	2.2±0.06	4.32±0.12	3.52±0.2	2.32±0.09	12.36±0.47
CNPs+I/R	2.1±0.04	4.0.2±0.11	2.95±0.18	2.72±0.1	11.34±0.43
TNG+I/R	1.95±0.03	3.95±0.12	2.75±0.13	2.15±0.14	10.8±0.42
TNG-CNPs+I/R	1.2±0.01^**$$	2.25±0.07^***$$$^ϕϕ	1.72±0.03^***$$ϕϕ	0.9±0.01^*$	6.07±0.12^***$$ϕϕ

Renal I/R-induced AKI has a poor prognosis despite advances in medical care (20). Our study indicated that TNG alone slightly improves renal insufficiency in the post-ischemic kidney in a rat model. Using TNG-CNPs enhanced reno protective effects against renal injury induced by renal (I/R).

Recent studies showed that injection of NO-releasing agents in low and sustained dosage induced superior recovery in renal ischemia through reoxygenation and increased the blood supply of kidney microvasculature (21-23). TNG is a NO-releasing agent commonly used as a vasodilator for conditions including cardiac surgery, pulmonary edema, and aortic dissection (23, 24). In this study, we loaded TNG in CNPs to eliminate the TNG-free drug side effects such as mitochondrial superoxide production and provided the sustained release profile.

A previous study conducted in our laboratory demonstrated that renal I/R injury is associated with increased oxidative stress (25). This experiment found that renal I/R induced oxidative stress, as confirmed by a significant increase in TOS and decreased TAC levels in the renal tissue. Oxidative stress has been demonstrated to play an essential role in the progression of renal I/R injury, and antioxidant agents have been reported as potential and suitable therapeutic molecules (26, 27).

Recent research has reported on the mechanism of the antioxidant effects of the modified nanoparticles in medicine (28, 29). Furthermore, the administration of the NO-releasing agent provided significant benefits in the renal I/R injury model. Najafi et al. combined NO-releasing features of S-nitroso-N-acetyl penicillamine (SNAP) with Fmoc-diphenylalanine (FmocFF-SNAP) hydrogels to explore its therapeutic efficiency on mice renal I/R injury model. Intralesional administration of FmocFF-SNAP significantly improves oxidative parameters, histopathological markers, and renal function factors (30). Our data shows that intraperitoneal injection of TNG-CNPs 30 minutes before renal ischemia can suppress oxidative status, characterized by decreased TOS and OSI indices and increased TAC levels. However, neither TNG nor CNP alone could change oxidative stress in the post-ischemic kidney.

Disturbed ROS homeostasis by an imbalance in ROS production and antioxidant defenses during ischemia and reperfusion leads to pathological changes in the kidney, which can impair renal function (31, 32). Intravenous administration of S-nitrosylated loaded in L-serine (Ser) modified polyamidoamine (PAMAM) dendrimer in mice renal I/R injury model inhibited plasma Cr elevation, histopathological changes, and AKI blood markers (33). Our histopathological analysis of the kidney demonstrated several findings of tissue changes, including tubular degeneration, enlargement of Bowman's spaces, vascular congestion, and formation of intratubular casts. In addition, the histological changes resulted in kidney dysfunction, as evidenced by a decline in the glomerular filtration rate and increased plasma levels of blood urea nitrogen and creatinine.

Vascular and tubular injury relieved by TNG-CNPs pretreatment. Consistent with these results, functional assays demonstrated a significant reduction in blood urea nitrogen and creatinine levels and a rise in glomerular filtration rate levels with TNG-CNPs pretreatment. In recent years, many pharmacological companies have received Food and Drug Administration (FDA) approval for using and developing NPs-based drugs (34). CNPs showed excellent antioxidative properties with major biocompatibility in AKI studies (35). We expected that TNG-CNPs might illustrate a promising alternative for AKI treatment.

Results of this study indicated that a single dose of TNG-CNPs protects the kidney against renal ischemia/reperfusion injury. TNG-CNPs alleviated the histological lesions of the kidney, accompanied by an increased glomerular filtration rate and decreased plasma creatinine and blood urea nitrogen levels. Our data suggest that the protective effect of TNG-CNPs against renal I/R injury is related to alleviating renal oxidative stress by increasing TAC levels and reducing TOS and OSI.

Acknowledgments

The authors would like to thank Shiraz University of Medical Sciences, Shiraz, Iran, and also the Center for Development of Clinical Research of Nemazee Hospital and Dr. Nasrin Shokrpour for editorial assistance.

Declaration of Competing Interest

There are none.

Funding

This study was supported by the Vice-Chancellor for Research, Shiraz University of Medical Sciences, Shiraz, Iran) (Academic Grant Number: 25487).

Authorship contribution statement

Z.K and A.GH conceptualization of the study, funding acquisition, methodology, and visualization. Z.K, P.GH, A.GH, and KH.A carried out the literature research performed the experimental parts, and prepared the figures and tables. Z.K, A.GH, and KH.A participated in software and formal analysis parts, writing - review & editing. All authors read, edited, and approved the final manuscript.

Data Availability

The data that support the findings of this study are available from the corresponding author, Dr. Ahmad Gholami, upon reasonable request.

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No competing interests reported.

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Trinitroglycerine-loaded Chitosan Nanoparticles Attenuate Renal Ischemia- Reperfusion Injury by Modulating Oxidative Stress

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