|Year : 2019 | Volume
| Issue : 1 | Page : 352-358
Therapeutic effects of human stem cells in experimentally induced acute kidney injury in rats
Mahmoud A El-Aziz Kora1, Ahmed M Zahran1, Ahmed R Tawfiq1, Yahya M. Naguib Abd El-Salam2, Hussain M Hussain Kholaif3
1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Physiology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Internal Medicine, Ashmoun Central Hospital, Menoufia, Egypt
|Date of Submission||30-Jul-2017|
|Date of Acceptance||08-Sep-2017|
|Date of Web Publication||17-Apr-2019|
Hussain M Hussain Kholaif
Ashmoun 24582, Menoufia Governorate
Source of Support: None, Conflict of Interest: None
The aim of this study was to evaluate the effect of stem cell therapy in drug-induced acute kidney injury in rats.
Acute kidney injury (AKI) is defined as a rapid decrease in renal functions within few days; thus drug-induced AKI is a frequent entity in clinical medicine. Stem cell therapy provides a hopeful prospective for injured tissues and for repairing damaged organs.
Materials and methods
A total of 30 male Swiss albino rats were used in the present study. The animals were randomly divided into three groups. Group I: control group (10 rats). Group II: AKI group (10 rats), gentamicin-induced AKI rat models were used. Group III: stem-cell-treated AKI group (10 rats). Rats with established AKI were injected with CD34-positive stem cells. The three studied groups were assessed for serum urea, blood urea nitrogen, serum creatinine, and kidney injury molecule 1 (KIM-1). At the end, all the rats were killed and their kidneys were excised for histopathology and immunohistochemical studies.
Serum KIM-1 level was significantly higher in the AKI group in comparison with both control group and stem-cell-treated group (P = 0.001), whereas no statistically significant difference was found between control group and stem-cell-treated group regarding serum KIM-1 level (P = 0.755). The results of the immunohistopathological studies have shown no significant changes between control group and AKI-stem-cell-treated group.
This study showed that AKI markers improved after treatment by stem cells in AKI-induced group.
Keywords: acute kidney injury, kidney injury molecule 1, rats, stem cell therapy
|How to cite this article:|
El-Aziz Kora MA, Zahran AM, Tawfiq AR, Abd El-Salam YM, Hussain Kholaif HM. Therapeutic effects of human stem cells in experimentally induced acute kidney injury in rats. Menoufia Med J 2019;32:352-8
|How to cite this URL:|
El-Aziz Kora MA, Zahran AM, Tawfiq AR, Abd El-Salam YM, Hussain Kholaif HM. Therapeutic effects of human stem cells in experimentally induced acute kidney injury in rats. Menoufia Med J [serial online] 2019 [cited 2019 Jul 17];32:352-8. Available from: http://www.mmj.eg.net/text.asp?2019/32/1/352/256123
| Introduction|| |
Acute kidney injury (AKI) is defined as a clinical syndrome characterized by a rapid decrease in renal function together with the accumulation of waste products such as urea . The incidence of non-dialysis-requiring AKI is ∼5000 cases per million people per year and the incidence of dialysis requiring AKI is 295 cases per million people per year. AKI complicates 1–7% of all hospital admissions and 1–25% of ICU admissions. Furthermore, AKI is known as an independent risk factor for mortality. AKI increases the risk of death by 10- to 15-fold and results in a mortality rate of 50% .
The kidneys are the major targets for the toxic effects of various chemical agents and thus drug-induced AKI is a frequent entity in clinical medicine. The incidence of nephrotoxic AKI is difficult to estimate due to the variabilities of patient populations and the criteria of AKI. However, nephrotoxicity has been reported to contribute to ∼8–60% of hospital-acquired AKI cases . In a recent large multicenter epidemiological survey performed on critically ill patients, drug nephrotoxicity was found to be responsible for 19% of AKI cases .
Stem cell therapy provides a hopeful prospective for injured tissues and organs repair . The therapeutic effect of mesenchymal stem cells (MSCs) was questioned in different animal models of renal disease, including cis-diaminedichloroplatinum (CDDP)-induced AKI . Among the different types of stem cells, bone marrow-derived mesenchymal stem cells (BM-MSCs) have gained great popularity. The proposed mechanism of action of MSCs could either be by replacing the damaged cells directly or indirectly through induction of cell regeneration, leading to an improvement in renal function and structure. However, the mechanism of MSCs against CDDP-induced AKI remains to be explained .
Circulating hematopoietic progenitor cells home to the damaged kidney by responding to injury signals that correspond to cognate surface receptors which they express . Accumulating evidence indicates that exogenously infused MSCs respond to similar homing signals. In mice, the expression of cluster of differentiation (CD44) and its major ligand hyaluronic acid mediates MSC migration to the injured kidney  and hyaluronic acid also promotes MSC dose-dependent migration in vitro. Liu et al.  have found that when administered systemically, MSCs home to the ischemic kidney, improving renal function, accelerating monogenic response, and reducing cell apoptosis, but these effects were abolished by either chemokine receptor type 4 (CXCR4) or CXCR7 inhibition, implicating the stromal-derived factor-1–CXCR4/CXCR7 axis in kidney repair .
Collectively, these observations suggest that strategies aimed to enhance MSC expression of homing signals may improve their capacity to attenuate renal dysfunction. Studies have shown that selective manipulation of MSCs before transplantation (preconditioning) enhances their ability to protect damaged tissues . Indeed, preconditioning with the mitogenic and prosurvival factor insulin-like growth factor-1 before systemic infusion of BM-MSCs upregulates the expression of CXCR4 and restores normal renal function in a mice model of gentamicin-induced AKI . The aim of our work was to study the effect of transplanted human stem cells in experimentally induced AKI in rats.
| Materials and Methods|| |
In this study, a total of 30 Swiss albino rats weighing ∼150–250 g were used. The animals were randomly divided into three groups. The rats were maintained under controlled temperature, humidity, and 12-h light/dark cycles. They were fed standard rodent chow and allowed free access to water ad libitum, and were kept for 10 days before any procedure to allow proper acclimatization. Animal care and use was approved by the Ethics Committee of the Faculty of Medicine, Menoufia University, Egypt. The experiments were carried in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication no. 85-23, revised in 1996).
Group I: control group (10 rats)
In this group, the rats received a single intravenous injection of normal saline 0.9% (vehicle of gentamicin) in the tail vein of rats. These rats were left to live normally for 5 weeks.
Group II: acute kidney injury group (10 rats)
AKI was induced in rats by single intravenous injection of gentamicin (Merck & Co. Inc., Kenilworth, New Jersey, USA) 5 mg/kg body weight in the rat tail vein . The rats were expected to be nephropathic 1 week after gentamicin injection.
Group III: acute kidney injury + stem-cell-treated group (10 rats)
Rat models of gentamicin-induced AKI were generated as mentioned before. A single dose of CD34-positive cells (in a dose of 2 × 106 cells/rat) was injected intravenously in the rat tail vein after 1 week of gentamicin injection . These rats were left to live in their cages for 4 weeks.
Blood sample collection
Blood samples were collected from the retro-orbital venous plexus, using a fine heparinized capillary tube introduced into the medial epicanthus of the rat's eye . Two milliliters of blood at room temperature was kept in a water bath for 10 min, and then centrifuged at 3000 rpm for 20 min The supernatant serum was collected in a dry, clean tube and kept at 80°C for the estimation of serum urea, creatinine, blood urea nitrogen, and kidney injury molecule 1 (KIM-1).
At the end of the experiment, all the rats were killed by decapitation and their kidneys were excised for histopathology by [hematoxylin-eosin (H and E) stain and Masson's trichrome technique], and for immunohistochemical studies by labeled streptavidin–biotin–horseradish peroxidase technique. Lumbar incision was done to excise the kidneys which were fixed in 4% paraformaldehyde and processed through paraffin embedding and were prepared for immunohistochemical studies.
Isolation of CD34-positive stem cells
Stem cell separation
Umbilical cord blood (UCB) was obtained at the end of full-term deliveries, whereas the placenta is still in utero, after clamping and cutting of the cord using strict aseptic techniques. The umbilical vein was cleansed with alcohol followed by betadine, then blood was drained into sterile collection tubes containing the anticoagulant citrate phosphate dextrose adenine l (∼10 ml) since the total collection was ∼100 ml. The UCB samples were collected separately and stored at 4°C and processed within 24 h .
Separation and purification of CD34+ hematopoietic stem cells/hematopoietic progenitor stem cells was carried out according to the method described by Milteny et al.  by the immunomagnetic separation technique using Dynabeads (Dynal, Oslo, Norway). Circulating hematopoietic progenitor cells home to the damaged kidney by responding to injury signals that correspond to cognate surface receptors which they express.
The UCB collection is excluded from women with known history of hepatitis, infectious diseases, diabetes mellitus, severe hypertension, abortions, or bad obstetric history.
Serum urea and creatinine were estimated using kits supplied by Diamond Diagnostic (Munchen, Germany). Serum blood urea nitrogen was estimated using the kit supplied by Siemens Healthcare Diagnostics (Malvern, Pennsylvania, USA) according to the manufactures' instructions. Serum KIM-1 was measured by specific enzyme-linked immunosorbent assay kit (ALPCO Diagnostic, Salem, New Hampshire, USA) as described by the manufacturer.
In this work, the mean, SD, SE, and the P value were calculated, post-hoc test was calculated. Data were fed to a computer using IBM statistical package for the social science, version 20 (IBM Corporation, Chicago, Illinois, USA). For Windows, MedCalc Software (BVBA, Ostend, Belgium) is used. Quantitative data were described using the mean and SD for normally distributed data. Analysis of variance test is used for differences among at least three groups.
| Results|| |
Serum creatinine level was significantly higher in the AKI group (1.41 ± 0.16 mg/dl) in comparison with both control group (0.32 ± 0.03 mg/dl) and stem-cell-treated group (0.40 ± 0.05 mg/dl) (P = 0.001), whereas no statistically significant difference was found between the control group and stem-cell-treated group regarding serum creatinine level (P = 0.102) [Table 1].
Serum urea level was significantly higher in the AKI group (123.2 ± 11.2 mg/dl) in comparison with both the control group (45.1 ± 5.66 mg/dl) and stem-cell-treated group (50.0 ± 7.72 mg/dl) (P = 0.001), whereas no statistically significant difference was found between the control group and stem-cell-treated group regarding serum urea level (P = 0.235) [Table 1]
Blood urea nitrogen was significantly higher in the AKI group (58.2 ± 5.56 mg/dl) in comparison with both control group (22.0 ± 1.58 mg/dl) and stem-cell-treated group (30.0 ± 5.31 mg/dl) (P = 0.001) and also high significant difference was found between the control group and the stem-cell-treated group regarding blood urea nitrogen level (P = 0.001) [Table 1].
Serum KIM-1 level was significantly higher in the AKI group (6.12 ± 0.59 ng/mg creatinine) in comparison with both control group (0.75 ± 0.08 ng/mg creatinine) and stem-cell-treated group (0.80 ± 0.10 ng/mg creatinine) (P = 0.001), whereas no statistically significant difference was found between the control group and stem-cell-treated group regarding serum KIM-1 level (P = 0.755) [Table 1].
Immunohistopathological study results
Examination of H and E-stained sections from the normal control kidney showed normal architecture in the cortex and in the medulla [Figure 1].
|Figure 1: Examination of hemotoxylin and eosin-stained section from the normal control kidney.|
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Examination of Masson's trichrome-stained sections from the normal control kidney showed scanty greenish-colored collagen fibers in the interstitium as well as in the mesangium [Figure 2].
|Figure 2: Examination of Masson's trichrome-stained section from the normal control kidney.|
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While H and E-stained sections from the kidneys of AKI-non-treated group showed that the affection was in the form of focal tubular necrosis, the renal corpuscles showed varying degrees of degeneration. The affected tubules showed coagulative necrosis [Figure 3].
|Figure 3: Examination of hemotoxylin and eosin-stained section from the kidney of acute kidney injury-non-treated group. The affected tubules showed coagulative necrosis|
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Examination of Masson's trichrome-stained sections of AKI-non-treated group showed an increase in the green-stained collagen fibers in the interstitium and in the area of focal tubular necrosis as well as in the mesangium [Figure 4].
|Figure 4: Examination of Masson's trichrome-stained section of acute kidney injury-non-treated group. Shows increase in the green-stained collagen fibers|
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H and E-stained sections from the AKI-stem-cell-treated group showed a picture nearly similar to the normal control group kidney [Figure 5].
|Figure 5: Examination of hemotoxylin and eosin-stained section from acute kidney injury-stem-cell-treated group.|
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Sections stained with Masson's trichrome technique from AKI-stem-cell-treated group showed scanty, greenish-colored collagen fibers in the interstitium and in the mesangium, a picture nearly similar to the normal control group [Figure 6].
|Figure 6: Examination of Masson's trichrome-stained section from acute kidney injury-stem-cell-treated group.|
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Immunohistochemical stained sections from AKI-stem-cell-treated group showed a positive brownish staining for the monoclonal mouse anti-human (CD45). The staining appeared granular in the cytoplasm and was observed only in the tubular cells; however, the glomeruli were not stained [Figure 7].
|Figure 7: Immunohistochemical stained section from acute kidney injury-stem-cell-treated group. The staining appeared granular in the cytoplasm and was observed only in the tubular cells; however, the glomeruli were not stained|
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| Discussion|| |
AKI is an abrupt loss of kidney function that develops within 7 days . AKI is an important cause of morbidity and mortality worldwide affecting more than 13 million people, especially in poor resource countries . In this study, serum creatinine level was significantly higher in the AKI group in comparison with both control group and stem-cell-treated group, whereas no statistically significant difference was found between the control group and the stem-cell-treated group regarding serum creatinine level. Moreover, serum KIM-1 level was significantly higher in the AKI group in comparison with both control group and stem-cell-treated group, whereas no statistically significant difference was found between the control group and stem-cell-treated group regarding serum KIM-1 level.
The histopathological results of AKI-induced group as seen with H and E staining explain the previous data as there was acute focal tubular necrosis with varying degrees of degeneration in the renal corpuscles. The percentages of affection (cloudy swelling, hydropic degeneration, and necrosis) of proximal convoluted tubules, distal convoluted tubules, and collecting tubules were significantly increased when compared with normal control group. Many of the tubules were filled with hyaline casts; desquamated epithelial cells were observed in the lumen of some tubules. The affected renal corpuscles had a variety of findings; most of them showed dilated glomerular capillaries and some showed an epithelial crescent. Few of the renal corpuscles were degenerated.
The histopathological results of the stem-cell-treated group confirmed the previous data as the percentages of affection (cloudy swelling, hydropic degeneration, and necrosis) of proximal convoluted tubules, distal convoluted tubules, and collecting tubules were significantly decreased when compared with AKI-non-treated group. In the present investigation, immunohistochemical stained sections from AKI-stem-cell-treated group showed a positive brownish staining for the monoclonal mouse anti-human CD45.
This demonstrated that BM-MSCs have been reported to maintain renal functions within normal levels in several AKI models including gentamycin-induced and cisplatin-induced AKI . Previous studies demonstrated that amelioration of CDDP nephrotoxicity can be achieved by inhibition of tissue necrosis factor α (TNF-α) production and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation. Therefore, the modulation of renal inflammatory reactions and apoptotic pathways after cisplatin or CDDP injection may help to prevent CDDP-induced nephrotoxicity .
In agreement with our study, the study by Ramesh and Reeves  reported that candesartan reduced the renal TNF-α and monocyte chemoattractant protein-1 (MCP-1) levels and renal expression of NF-κB in CDDP-treated rats when compared with normal rats. Conceding with our findings, candesartan suppressed the renal MCP-1 and NF-κB in a model of chronic kidney disease. Cheng et al.  have shown the anti-inflammatory effects of candesartan through a direct antioxidant action independent of angiotensin receptor inhibitors. They postulated that candesartan has the ability to inhibit the production of reactive oxygen species and to correct the redox imbalance induced by TNF-α.
Their study observed that there was a significant reduction in mitogen-activated protein kinase (p38-MAPK), caspase-3, and Bax renal expressions, indicating the nephron-protective effect of candesartan by its antiapoptotic effects. These encouraging results support those reported by Lv et al.  who documented the antiapoptotic activity of candesartan by blocking the mesangial cell oxidative stress and apoptosis induced by angiotensin II.
Regarding the recent findings on BM-MSCs, they documented that injection of BM-MSCs showed a significant reduction in the renal levels of TNF-α and MCP-1 levels and renal expression of NF-κB in CDDP-treated rats when compared with normal rats. It was found that BM-MSCs significantly lowered renal gene expression of TNF-α in a model of experimental diabetic nephropathy. Moreover, BM-MSCs significantly lowered the renal MCP-1 in rats treated with MSCs and gentamicin when compared with rats administered gentamycin alone in a model of gentamicin-induced AKI .
The anti-inflammatory and antifibrotic activities of BM-MSCs were indicated by attenuation of the TNF-α and NF-κB overexpression in a recent model of albumin-induced renal tubular inflammation and fibrosis. The MSCs have a prominent immunomodulatory property that leads to the downregulation of inflammatory reactions .
Moreover, BM-MSCs also significantly suppressed the renal p38-MAPK, caspase-3, and Bax expressions in CDDP-treated rats. Our results are similar to these findings of Qi and Wu  who observed downregulation of Bax, p38-MAPK, and caspase-3 in CDDP-treated rats administered BM-MSCs as compared with the CDDP-treated rats administered saline.
The possibilities of the therapeutic potential of MSCs were either direct effect by replacing damaged cells or indirect effect through signals and induction of cellular regeneration. The transplanted MSCs were able to cause release of various factors with its beneficial antiapoptotic, anti-inflammatory, mitogenic, or angiogenic properties .
In agreement with our study, Morigi et al.  have injected human UCB-derived MSCs to immunodeficient mice with cisplatin-induced acute tubular injury. They demonstrated that these cells ameliorated tubular injury, resulting in the recovery of renal function. They also cocultured UCB-derived MSCs with cisplatin-treated proximal tubular cells and human kidney-2 cells and demonstrated that the expression of the hepatocyte growth factor was particularly induced and that of interleukin 1β and tumor necrosis factor-α was significantly decreased in the coculture system.
In the study by Reiss et al. , the animals were treated with gentamicin injections for up to 20 days to establish the time point of the gentamicin treatment that best reproduces what is observed in clinical practice. The treatment with gentamicin for 10 days was able to induce AKI  with an increase in serum creatinine, urea, fractional excretion of sodium, and apoptosis and decrease in cell proliferation. In addition, there was an increase in the proinflammatory and a decrease in the anti-inflammatory plasmatic cytokines that reflect the inflammatory process induced by gentamicin in the kidney. These results are in agreement with the findings of other studies .
Reis et al.  have also evaluated that bone marrow stromal cells (BMSCs) could prevent AKI caused by gentamicin. It was observed that when BMSCs were administrated before treatment with gentamicin on the fifth day of treatment, the full impact of gentamycin on the kidney was not blunted. Previous studies have shown that on the fifth day of treatment with gentamicin, renal injury is already present and BMSCs may be recruited to the injury site but not at a level sufficient to produce a protective effect.
The functional protection by BMSCs can be the consequence of the capacity of these cells to engraft the damaged kidney. Reiss et al.  have evaluated the presence of BMSCs in renal tissue by using the chromosome Y localization strategy. It was detected in all analyzed groups, indicating that BMSCs migrate to the local site of the injury and stay during continuous injury period. However, chromosome Y was not detected in the prevention group 24 h before the insult with gentamicin, suggesting that the BMSCs were rapidly removed because no lesions were present in renal tissue to allow for the docking of stem cells. These results suggest that BMSCs might be able to protect the injured tissue potentially by releasing factors with repair proprieties .
| Conclusion|| |
We found that there was a positive significant correlation between the AKI group and both control and stem-cell-treated group regarding serum creatinine, serum urea, blood urea nitrogen, and serum KIM-1. This study showed that AKI markers and renal pathology improved in gentamicin-induced AKI group after treatment with human MSCs by stem cell transplantation.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]