Bone marrow-derived c-kit positive stem cell administration protects against diabetes-induced nephropathy in a rat model by reversing PI3K/AKT/GSK-3β pathway and inhibiting cell apoptosis

doi:10.21203/rs.3.rs-2737869/v1

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Research Article

Bone marrow-derived c-kit positive stem cell administration protects against diabetes-induced nephropathy in a rat model by reversing PI3K/AKT/GSK-3β pathway and inhibiting cell apoptosis

https://doi.org/10.21203/rs.3.rs-2737869/v1

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published 02 May, 2023

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Stem cell-based therapy has been proposed as a novel therapeutic strategy for diabetic nephropathy. This study was designed to evaluate the effect of systemic administration of rat bone marrow-derived c-kit positive (c-kit⁺) cells on diabetic nephropathy in male rats, focusing on PI3K/AKT/GSK-3β pathway and apoptosis as a possible therapeutic mechanism. Twenty-eight animals were randomly classified into four groups: Control group (C), diabetic group (D), diabetic group, intravenously received 50 μl phosphate-buffered saline (PBS) containing 3×10⁵ c-kit^- cells (D+ckit^-); and diabetic group, intravenously received 50 μl PBS containing 3×10⁵ c-Kit positive cells (D+ckit⁺). Control and diabetic groups intravenously received 50 μl PBS. C-kit⁺ cell therapy could reduce renal fibrosis, which was associated with attenuation of inflammation as indicated by decreased TNF-α and IL-6 levels in the kidney tissue. In addition, c-kit⁺ cells restored the expression levels of PI3K, pAKT, and GSK-3β proteins. Furthermore, renal apoptosis was decreased following c-kit⁺ cell therapy, evidenced by the lower apoptotic index in parallel with the increased Bcl-2 and decreased Bax and Caspase-3 levels. Our results showed that in contrast to c-kit^– cells, the administration of c-kit⁺ cells ameliorate diabetic nephropathy and suggested that c-kit⁺ cells could be an alternative cell source for attenuating diabetic nephropathy.

Diabetic nephropathy

Renal fibrosis

PI3K/AKT/GSK3β signaling

Apoptosis

c-kit positive stem cell

Diabetes mellitus is chronic physiological dysfunction associated with an inability to produce adequate insulin or impaired insulin function [1]. Micro and macroangiopathy induced by chronic hyperglycemia impairs the functions of body organs and eventually leads to cardiomyopathy, retinopathy, neuropathy, and nephropathy [2, 3]. Nephropathy has been reported as a severe microvascular complication, leading to end-stage renal disease and mortality in diabetic patients [4]. It has been estimated that about 25-40% of diabetic patients exhibit nephropathy [5]. A number of pathophysiological processes, such as inflammation and oxidative stress, are involved in the cellular and molecular mechanisms of diabetic tissue injuries [6]. Hyperglycemia has been shown to exacerbate oxidative stress via induction of non-enzymatic glycosylation pathways and production of advanced glycosylation end products (AGEs), protein kinase C (PKC), and sorbitol pathway of glucose metabolism [7-9]. Moreover, oxidative stress plays a key role in the development of diabetic nephropathy by activating the apoptosis process [10].

Apoptosis is a mode of regulated cell death leading to the loss of kidney podocytes, epithelial and tubular cells, and finally, gradual loss of renal function in chronic hyperglycemic conditions [11]. It has been revealed that the apoptosis process is mediated by a set of intracellular pathways, including the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway [12]. The AKT signaling pathway contributes to cell viability by limiting apoptosis and promoting cell proliferation [13]. AKT activation is downregulated in hyperglycemic conditions, which is accompanied by enhanced inflammatory markers, caspase-3 activation, and renal dysfunction [14]. Thus, induction of AKT signaling has been proposed as a potential therapeutic target in diabetic nephropathy [14]. As a correlate, suppression of apoptosis in diabetic nephropathy has been shown to be associated with reduced levels of inflammatory factors, including IL-6 and TNF-α, and activation of the PI3K/AKT/GSK-3β signaling pathway [15]. In addition, altered levels of Bax and Bcl2, two apoptosis-related molecules, enhances the permeability of mitochondrial membranes to cytochrome C following oxidative injury and thereby activate caspase proteins, especially caspase-3, which serve an essential role in executing apoptosis [16-18].

Recently, stem cell-based therapy has been proposed to alleviate kidney pathologies, including experimental diabetic nephropathy [19]. However, the mechanisms that mediate stem cell therapy in nephropathy have not been clearly elucidated [20].

C-kit⁺ cells are bone marrow-derived and tissue stem cells express the marker kit, the cell surface receptor with tyrosine kinase activity [21]. Several studies have documented the alleviating effects of c-kit⁺ cells in various pathologies [21-23]. The present study sought to evaluate the effects of systemic administration of bone marrow-derived c-kit⁺ cells on diabetes-induced renal injury with a focus on inflammation, PI3K/AKT/GSK-3β signaling pathway, and renal apoptosis in the type 2 diabetes models of rats.

Experimental design

Thirty-eight healthy male Wistar rats (10 weeks old, weighing 200–250 g) were acclimatized for seven days and were kept at 22 °C ± 2 °C with 12 hr light/dark cycle. Ten rats were randomly selected for the isolation of c-Kit⁺ cells from bone marrow. Twenty-eight animals were randomly assigned to four following groups (n=7): healthy rats (C group), intravenously received 50 μl phosphate-buffered saline (PBS); diabetic rats, intravenously received 50 μl PBS (D group); diabetic rats, intravenously received 50 μl PBS containing 3×10⁵ c-kit negative cells (D+ckit^-group); and diabetic rats, intravenously received 50 μl PBS containing 3×105 c-kit positive cells (D+ckit⁺ group). Experimental procedures and time scales are presented in Fig. 1.

Induction of experimental type 2 diabetes

To induce diabetes, animals were fed ad libitum with a high-fat diet (HFD) (58% fat, 17% carbohydrate, and 25% protein) for four weeks, followed by an intraperitoneal injection of a single dose of STZ (35 mg/kg body weight, dissolved in a 0.1 mol/L citrate buffer). After five days of STZ injection, the animals that showed fasting blood glucose levels above 250 mg/dl were included in the study [24].

C-kit cells enrichment

Ten rats were anesthetized using a surplus dose of Ketamine and Xylazine. After cervical dislocation, the extremities of the femurs were cut, and medullary content was extracted by pushing PBS containing 2% fetal bovine serum (FBS; Gibco). Mononuclear cells (MNCs) were isolated using gradient centrifugation Ficoll-Paque^® solution (Sigma-Aldrich). The samples were centrifuged at 400 g for 20 min, and monolayer cells were collected and washed twice for 5 minutes. The cells were incubated in PBS (1% FBS) at 4 °C for 30 min. The supernatant was removed, and the cells were incubated with anti-c-Kit microbeads according to the manufacturer's instructions. At the end of the procedure, c-kit⁺ and c-kit^- cells were isolated by passing through the LS columns (Miltenyi Biotec, Germany) [25].

Cell labeling

The cells were labeled by incubation with Cell Tracker™ CM-Dil. In brief, the cells were exposed to Cell Tracker™ CM-Dil (20 µM) and incubated for 20 min followed by three times washes with PBS. About 3 × 10⁵ cells were intravenously administrated in both D+ckit^- and D+ckit⁺ groups [26].

Tissue sampling

Four weeks after the treatment, the rats were euthanized after an overdose of ketamine and xylazine. After decapitation, kidneys were immediately isolated and washed thoroughly with normal saline. The right kidneys were kept at -80º^C until processing for biochemical studies. The left kidneys were fixed with 10% formaldehyde for histological analysis.

Masson-trichrome staining for detecting tubulointerstitial fibrosis

The left Kidneys were fixed with 10% formaldehyde for 48 h, then embedded in paraffin and cut into five μm sections. The sections were deparaffinized and rehydrated through ethanol (100%, 95%, and 70%), and stained with Weigert's iron hematoxylin for 10 minutes. Next, staining with Biebrich scarlet-acid fuchsin solution was performed and the sections were differentiated in the phosphomolybdic-phosphotungstic acid solution. The sections were then transferred to aniline blue solution, stained for 5-10 minutes, rinsed briefly in distilled water, and differentiated in 1% acetic acid solution for 2-5 minutes. After washing in distilled water, the samples were dehydrated quickly through 95% and absolute ethanol and cleared in xylene. Finally, mounting with a resinous mounting medium was done to obtain images using a microscope camera. The percentage of blue staining area in the total area was analyzed using digital image analysis [27].

TUNEL assay

Apoptotic cells were detected and quantified by using a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay kit (E-CK-A334; Elabscience Biotechnology, Inc.) following the manufacturer's instructions. Briefly, the paraffin slices were dewaxed and hydrated by ethanol, then washed with PBS 3 times, 5 min each time. Proteinase K working solution was added to the slides and incubated at 20~37°C for 15~30 min. Again the slides were washed with PBS three times, 5 min each time. 100 μL of TdT Equilibration working buffer was added to each slide and incubated at room temperature for 30 min. 50 μL of TdT Enzyme was added to each slide and incubated at 37°C for 60 min in a wet bow. After washing the slide with PBS 3 times, 4′,6-diamidino-2-phenylindole (DAPI) was added to counterstain the nuclei, followed by incubation at room temperature for 5 min. Finally, a mounting medium (containing fluorescent mounting media) was added to seal the slides. The dried sections were observed with fluorescence microscopy (Olympus BX50), and the images were taken by a camera (Olympus DP72) from five random fields. The apoptotic index was calculated as follows [28]:

The apoptotic index = (positively stained apoptotic cells)/ (total number of cells) × 100%.

Immunoblotting

Western blotting method was used to detect protein levels of TNF-α, IL-6, PI3K, AKT, pAKT, GSK-3β, Bax, Bcl-2, Procaspase-3, and cleaved Caspase-3 in the kidney tissue of animals. For this purpose, 50 mg of kidney tissues were lysed in lysis buffer (500µL, Tris-HCL, pH=8, 0.003 gr EDTA, 0.08 gr NaCl, 0.025 gr Sodium Deoxycholate, 0.01 gr SDS, one tablet Protease inhibitor cocktail, 10 µl Triton NP40 (1%)) and then homogenized. The supernatant was obtained by centrifugation at 12,000×g for 10 min at 4 °C and stored at −20 °C. Each sample lysate was separated by 10% SDS-PAGE and transferred to 0.2-μm PVDF membranes following electrophoresis. After blocking with 5% (w/v) nonfat dry milk in Tris-buffered saline, the membranes were incubated in antibody buffer with primary antibodies for 2h at room temperature, followed by incubation of blots with a secondary antibody in antibody buffer for 1h at 37 °C. According to the manufacturer's instructions, immunoblotting bands were visualized using enhanced chemiluminescence (ECL) detection kit. The band intensities were quantified using Image J software and normalized against β-actin as a housekeeping protein [29].

Statistical analysis

All quantitative results are expressed as means ± standard errors of the mean (SEMs). The statistical analyses were conducted using GraphPad Prism 9 (GraphPad Software, Inc. San Diego, CA, USA). One-way analysis of variance (ANOVA) was used to detect the significant difference between experimental groups, followed by Tukey's post-hoc test. Two-way ANOVA followed by Tukey's post-hoc test was used for data analyses of body weight and blood glucose levels. P < 0.05 was considered statistically significant in all results.

Body weight and blood glucose levels in the experimental groups

As shown in Fig. 2A, a significantly increased body weight was observed in diabetic groups, including the D group (p<0.05), D+ckit^-group(p<0.05), and D+ckit⁺ group (p<0.01) compared with the control group. Notably, there were no significant differences between D+ckit^- and D+ckit⁺ groups compared with the D group.

In addition, Fig. 2B illustrates the fasting blood glucose (FBS) levels in animal groups during the study. The results showed that after induction of type 2 diabetes, the levels of FBS in D, D+ckit^-, and D+ckit⁺ groups were significantly (p<0.001) increased in comparison to the control group. No significant differences in FBS were found between D+ckit^- and D+ckit⁺ groups compared with the D group.

C-kit⁺ cells were able to alleviate renal tubulointerstitial fibrosis

The renal tubulointerstitial fibrosis was evaluated using Masson's trichrome staining (Fig. 3), which revealed that there were significant (p<0.01) fibrotic areas detected by blue staining in D and D+ckit^- groups as compared with the control group. However, the mean area percentage of Masson trichrome positive tissue significantly (p<0.05) reduced in D+ckit⁺ groups compared with the D group.

C-kit⁺ cells modulated the levels of TNF-α and IL-6 in the kidney tissue of diabetic rats

The levels of TNF-α and IL-6 were measured in diabetic rats after transplantation of c-kit⁺ and c-kit^- cells (Fig. 4). Compared with control rats, we found significantly higher levels of TNF-α (p<0.01) and IL-6 (p<0.001) in the kidney of the diabetic group. Interestingly, a significant decrease in TNF-α (p<0.05) coincided with decreased IL-6 level (p<0.01) was notified in diabetic rats that received c-kit⁺ cells compared with the D group. No significant differences were found in the kidney levels of TNF-α and IL-6 in the D+ckit^- groups.

C-kit⁺ cell administration reverts the effect of Diabetes on PI3K/AKT/GSK3β

Western blot analysis showed that diabetes induction significantly (p<0.01) decreased the expression of PI3K, an effect that was significantly (p<0.05) reverted by c-kit⁺ cells (Fig. 5A). Diabetes also induced a marked decrease (p<0.01) in AKT phosphorylation (pAKT). However, c-kit⁺ cell injection significantly (p<0.05) reversed the downregulation of pAKT levels induced by hyperglycemia (Fig. 5C). Moreover, diabetes decreased (p<0.01) the levels of phosphorylated GSK3β, which significantly (p<0.05) reverted by c-kit⁺ cell therapy (Fig. 5D). Together, these findings suggest that diabetes-induced downregulation of the PI3-K/AKT/GSK3β pathway in the kidney and that administration of c-kit⁺ cell, but not c-kit^- cells, recovers this pathway.

C-kit⁺ cells decreased diabetes-induced apoptosis in the kidney tissue

TUNEL assay

TUNEL staining revealed that the renal apoptotic index significantly (p<0.001) enhanced in the D and D+ckit^- groups as compared with the control group. However, the rate of apoptosis significantly (p<0.05) reduced in the c-kit⁺-treated group compared to the diabetic group (Fig. 6).

The levels of apoptotic markers

To evaluate whether c-kit⁺ cell administration could alter apoptosis in the kidney tissue of experimental groups, we further measured the expression levels of Bax, Bcl-2, Caspase-3, and Procaspase-3 (Fig. 7). The data showed a significant (p<0.001) reduction in the expression levels of Bcl-2 in the D group which was reversed by c-kit⁺ cell injection (p<0.05). In contrast, Bax levels were significantly increased in the kidney of the diabetic group (p<0.001) as compared with the C group. However, this protein level was significantly (p<0.01) reduced in the D+ckit⁺ group as compared to the D group. In addition, Caspase-3 expression showed a significant (p<0.01) increase in the D group in comparison to the C group. Of note, Caspase-3 was suppressed in the kidney of the D+ckit⁺ group (p<0.05).

Although progenitor/stem cell therapy has been proposed as a regenerative strategy in kidney disease treatment, there are many questions about the cell delivery route for kidney repair [30]. It has been suggested that the delivery of cells should be performed considering the target tissue status [31]. Several studies have demonstrated intravenous stem cell administration as a safe route for the treatment of different kidney pathologies, such as diabetic nephropathy in human subjects [32, 33]. Accordingly, c-Kit⁺ cells were injected into diabetic nephropathy rats via the tail vein in the current study.

Our results indicate that diabetes induction in adult rats caused an increase in the levels of renal inflammatory factors TNF-α and IL-6, which are associated with reduced PI3K, pAKT, and GSK3β levels and increased apoptosis markers. Interestingly, systemic transplantation of c-kit⁺ cells, but not c-kit^- cells, could revert these changes in the diabetic kidney, suggesting a novel mechanism of action of c-kit⁺ cells in alleviating diabetic nephropathy. C-kit⁺ cells are a population of progenitor/stem cells that exhibit potential restoration features in different pathological conditions, especially in cardiac tissue [34, 35].

The therapeutic effects of stem cells have been reported in previous studies. However, understanding the underlying mechanisms seems to be necessary to develop therapeutic approaches [36]. Previously conducted studies have surveyed the potency of mesenchymal stem cells during several kidney diseases in animal models and clinical trials [37, 38]. In experimental models of diabetic nephropathy, it has been revealed that stem cells could be eligible to modulate renal histology and cell injuries [39, 40]. Furthermore, several studies have shown that bone marrow-derived mesenchymal stem cells improve interstitial fibrosis and inflammation in animal models of glomerular injuries [41-43]. Administration of mesenchymal stem cells also reduced glomerular and podocyte injury in diabetic models [44]. Zhang and colleagues have reported that glomerulus hypertrophy, tubular interstitial damage, and protein excretion could be attenuated in diabetic rats following intravenous injection of adipose-derived stem cells even at the progressive stage of diabetic nephropathy in rats [45]. Particularly, regeneration of tubular epithelial cells in the ischemia-reperfusion injury model and restoration of foot processes of podocytes in a rat model of acute proteinuria has been evident following kidney-derived c-kit⁺ cells transplantation [46]. In an animal model of acute proteinuria with podocyte damage, it has also been reported that kidney-derived c-kit⁺ stem cells could improve podocyte function and glomerular pathology through paracrine effects [47]. Along with these findings, our data revealed that bone marrow-derived c-kit⁺ cells could improve histological changes and renal fibrosis in a diabetic nephropathy model.

Stem cell transplantation could restore renal function, possibly by repairing the cell injuries, modulation of inflammatory status and immune response, and reducing fibrosis in diabetic nephropathy [44]. In support of the anti-inflammatory actions of bone marrow c-kit cells, we showed that the levels of inflammatory factors TNF-α and IL-6 were reduced in the kidney tissue of diabetic rats following c-kit⁺ cell systemic transplantation. Previous studies have evidenced the anti-inflammatory property of mesenchymal stem cells, which was accompanied by reduced secretion of inflammatory factors such as IL-6 and TNFα in the kidney [48-50]. Bone marrow-derived mesenchymal stem cells have also exhibited anti-inflammatory effects by upregulation of systemic anti-inflammatory cytokines such as epidermal growth factor (EGF) and IL-10 in the rat model of diabetes-induced nephropathy [51]. In addition, Corti et al. unveiled the neuroprotective effect of bone marrow-derived c-kit⁺ cells on degenerating motor neurons through anti-inflammatory function in a mouse model of amyotrophic lateral sclerosis [52]. It has been suggested that the trophic effect could be a major mechanism for the therapeutic properties of stem cell transplantation [53, 54] by which stem cells promote cytoprotective, anti-inflammatory, and immune regulatory effects in a paracrine, endocrine, or autocrine manner and thus involved in improving diabetic nephropathy [55].

Apoptosis has been observed in the diabetic kidney of experimental models [56] and is suggested to play an essential role in the loss of renal mass in diabetic patients [57]. In the present study, the diabetic condition significantly increased apoptosis rate and expression levels of Bax and Caspase-3 and decreased expression levels of Bcl2 in the kidney tissue. The infusion of bone marrow-derived c-kit⁺ cells attenuated the apoptosis rate and reversed the levels of Bcl2, Bax, and cleaved Caspase-3 proteins. These findings suggested that the renoprotective effects of bone marrow-derived c-kit⁺ cells may, in part, be mediated by antiapoptotic function. In support of our results, several studies have evidenced the antiapoptotic properties of stem cells in different kidney diseases [58-61]. Administration of bone marrow-derived mesenchymal stem cells has attenuated renal damage by increasing Bcl-2 and decreasing Bax protein in the rat model of diabetic nephropathy [62]. Another study also showed similar renal changes in cellular apoptosis rate and Bax and Bcl-2 levels following intravenous administration of adipose-derived mesenchymal stem cells [63]. Similarly, in acute kidney injury, the renoprotective effect of mesenchymal stem cells has been associated with suppressed apoptosis as indicated by increased expression of Bcl2 and downregulation of Bax protein [64].

The possible explanation for the improvement of diabetic nephropathy demonstrated in our study is the attenuation of apoptosis in the kidneys of animals that received c-kit⁺ cells. C-kit dysfunction has been shown to exacerbate apoptosis in cardiomyocytes following myocardial infarction [22], and conversely, reversing c-kit signaling could inhibit apoptosis in injury models in cortical neurons and myocardial cells [65, 66]. Moreover, several studies have evidenced that c-kit⁺ cell therapy could reduce cardiomyocyte apoptosis by paracrine factors, including AKT and Bcl-2, in myocardial infarction models [65, 67, 68].

As a correlate, suppression of apoptosis in diabetic nephropathy has been shown to be associated with reduced levels of inflammatory factors, including IL-6 and TNF-α, and activation of the PI3K/AKT/GSK-3β signaling pathway [15]. Several studies have evidenced the activation of different downstream pathways, especially the PI3K-AKT pathway, following the activation of the c-kit receptor in different cell types [69, 70]. In addition, c-kit receptor activation promotes the survival and migration of human cardiac progenitor cells, which have been revealed to be mediated by the PI3K-AKT pathway [35]. The PI3K/AKT pathway promotes cell survival processes in response to extracellular signals. The phosphorylated PI3K activates the AKT protein, which mediates a series of physiological functions, such as cell differentiation and apoptosis [71]. It has been revealed that AKT activation could increase anti-apoptotic capacity in diabetic tissues, and the impaired PI3K/AKT signaling pathway plays a fundamental role in the pathogenesis of diabetic nephropathy [72]. Thus, the downregulation of PI3K/AKT results in apoptosis in tubular cells of diabetic kidneys [73]. In addition, activation of GSK-3β by phosphorylated AKT promotes the apoptotic pathway by reducing the level of Bcl-2 and enhancing the level of Bax protein, which is subsequently associated with higher levels of cleaved caspase-3 [74].

Previously it has been documented that c-kit promotes pancreatic β-cell survival by the upregulation of the PI3K/AKT signaling pathway [70]. Ayach et al. reported that the mutant mice, when treated with bone marrow stem cells derived from c-kit⁺ donors, showed higher levels of AKT mRNA in the myocardial infarction model [65]. Considering these data, to elucidate the mechanisms by which c-kit cells exert renoprotective effects in chronic hyperglycemia, we evaluated PI3K/AKT/GSK-3β pathway in the diabetic kidney. In the current study, type 2 diabetic models showed downregulated the PI3K/AKT pathway activity, inhibited the expression of GSK-3β, reduced the levels of Bcl-2, and increased the levels of Bax and cleaved caspase-3. Our data demonstrated that the administration of c-kit⁺ cells could reverse the diabetes-induced inhibition of the PI3K/AKT/GSK-3β pathway and subsequently suppress apoptosis in kidney tissue as indicated by decreased Bax and cleaved caspase-3 and enhanced Bcl-2 levels.

In addition to the differentiation of c-kit⁺ cells into renal structures such as tubules and podocytes, paracrine mechanisms are also involved in the regenerative effects of these cells in kidney tissues, leading to morphological and functional improvement [30, 46]. In an animal model of acute proteinuria with podocyte damage, it has been reported that kidney-derived c-kit⁺ stem cells could improve podocyte function and glomerular pathology through paracrine effects [47]. Furthermore, c-kit receptor activation exerts anti-apoptotic effects in a paracrine manner attributed to the induction of AKT protein expression in target cells [75]. It is noteworthy that upregulation of the AKT expression as an anti-apoptotic agent also contributes to the expanded resident progenitor cells [76]. Resident c-kit⁺ cells are able to restore the integrity of the kidney and improve its structure and function [77]. Thus, activating resident progenitor cells by c-kit⁺ cells may be mediated by paracrine communication between recipient and donor cells [23]. Based on these data, the possible effect of exogenous c-kit⁺ cells on resident c-kit⁺ cells should also be considered to predict therapeutic outcomes [31].

The findings of the present study suggested that c-kit⁺ cell therapy may be efficacious in promoting diabetic nephropathy. We showed that systemic administration of bone marrow-derived c-kit⁺ cells reverted renal fibrosis, reduced inflammatory markers, upregulated PI3K, pAKT, and GSK3β proteins, and decreased apoptosis in an experimental nephropathy model. Thus, it is speculated that c-kit⁺ stem cell transplantation may be a potent therapeutic strategy for diabetes-induced nephropathy.

Funding

This study was supported by a grant from the Stem Cell Research Center of Tabriz University of Medical Sciences, Tabriz, Iran (Grant number 68029).

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

Conceptualization: Arshad Ghaffari-Nasab, Fariba Ghiasi, Rana Keyhanmanesh, Leila Roshangar, Elnaz Salmani Korjan, Navid Nazarpoor, and Fariba Mirzaei Bavil; Resources: Fariba Mirzaei Bavil; Supervision: Fariba Mirzaei Bavil; Data curation: Elnaz Salmani Korjan and Navid Nazarpoor; Formal analysis and investigation: Arshad Ghaffari-Nasab and Fariba Ghiasi; Methodology: Arshad Ghaffari-Nasab, Rana Keyhanmanesh, and Leila Roshangar; Validation: Fariba Ghiasi, Rana Keyhanmanesh, Leila Roshangar, and Fariba Mirzaei Bavil; Writing- Original draft preparation: Arshad Ghaffari-Nasab.

Data Availability

The data that support the findings of this study are available on request from the corresponding author.

Ethics approval

All procedures of the study were done in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institute of Health (NIH publication no. 85–23, revised 1996) and approved by the regional ethics committee of Tabriz University of Medical Sciences (No: IR.TBZMED.VCR.REC.1400.278).

Deepthi B, Sowjanya K, Lidiya B, Bhargavi R and Babu P (2017) A modern review of diabetes mellitus: an annihilatory metabolic disorder. J In Silico In Vitro Pharmacol 3. https://doi.org/10.21767/2469-6692.100014
Ghaffari-Nasab A, Bavil FM, Ghiasi R, Sadigh-Eteghad S and Alipour MR (2018) Effects of IMOD™ on angiogenesis, miR-503 and CDC25 expression levels in heart tissue of diabetic male rats. Avicenna journal of phytomedicine 8:152. https://doi.org/10.22038/ajp.2017.23107.1856
Samra YA, Said HS, Elsherbiny NM, Liou GI, El-Shishtawy MM and Eissa LA (2016) Cepharanthine and Piperine ameliorate diabetic nephropathy in rats: role of NF-κB and NLRP3 inflammasome. Life Sciences 157:187-199. https://doi.org/10.1016/j.lfs.2016.06.002
Selby NM and Taal MW (2020) An updated overview of diabetic nephropathy: Diagnosis, prognosis, treatment goals and latest guidelines. Diabetes Obes Metab 22 Suppl 1:3-15. https://doi.org/ 10.1111/dom.14007
Duran-Salgado MB and Rubio-Guerra AF (2014) Diabetic nephropathy and inflammation. World J Diabetes 5:393-8. https://doi.org/10.4239/wjd.v5.i3.393
Dirnagl U, Iadecola C and Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22:391-7. https://doi.org/10.1016/s0166-2236(99)01401-0
Paneni F, Beckman JA, Creager MA and Cosentino F (2013) Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur Heart J 34:2436-43. https://doi.org/10.1093/eurheartj/eht149
Eremina V, Cui S, Gerber H, Ferrara N, Haigh J, Nagy A, Ema M, Rossant J, Jothy S and Miner JH (2006) Vascular endothelial growth factor a signaling in the podocyte-endothelial compartment is required for mesangial cell migration and survival. Journal of the American Society of Nephrology 17:724-735. https://doi.org/10.1681/ASN.2005080810
Navarro-González JF, Mora-Fernández C, De Fuentes MM and García-Pérez J (2011) Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nature Reviews Nephrology 7:327-340. https://doi.org/10.1038/nrneph.2011.51
Sifuentes-Franco S, Padilla-Tejeda DE, Carrillo-Ibarra S and Miranda-Diaz AG (2018) Oxidative Stress, Apoptosis, and Mitochondrial Function in Diabetic Nephropathy. Int J Endocrinol 2018:1875870. https://doi.org/10.1155/2018/1875870
Verzola D, Gandolfo MT, Ferrario F, Rastaldi MP, Villaggio B, Gianiorio F, Giannoni M, Rimoldi L, Lauria F, Miji M, Deferrari G and Garibotto G (2007) Apoptosis in the kidneys of patients with type II diabetic nephropathy. Kidney Int 72:1262-72. https://doi.org/10.1038/sj.ki.5002531
Mattioli B, Giordani L, Quaranta MG and Viora M (2009) Leptin exerts an anti-apoptotic effect on human dendritic cells via the PI3K-Akt signaling pathway. FEBS Lett 583:1102-6. https://doi.org/10.1016/j.febslet.2009.02.029
Patel RK and Mohan C (2005) PI3K/AKT signaling and systemic autoimmunity. Immunol Res 31:47-55. https://doi.org/10.1385/IR:31:1:47
Rane MJ, Song Y, Jin S, Barati MT, Wu R, Kausar H, Tan Y, Wang Y, Zhou G and Klein JB (2010) Interplay between Akt and p38 MAPK pathways in the regulation of renal tubular cell apoptosis associated with diabetic nephropathy. American Journal of Physiology-Renal Physiology 298:F49-F61. https://doi.org/10.1152/ajprenal.00032.2009
Jing D, Bai H and Yin S (2017) Renoprotective effects of emodin against diabetic nephropathy in rat models are mediated via PI3K/Akt/GSK‑3β and Bax/caspase‑3 signaling pathways. Experimental and therapeutic medicine 14:5163-5169. https://doi.org/10.3892/etm.2017.5131
Lee SC and Pervaiz S (2007) Apoptosis in the pathophysiology of diabetes mellitus. Int J Biochem Cell Biol 39:497-504. https://doi.org/10.1016/j.biocel.2006.09.007
Allen DA, Yaqoob MM and Harwood SM (2005) Mechanisms of high glucose-induced apoptosis and its relationship to diabetic complications. J Nutr Biochem 16:705-13. https://doi.org/10.1016/j.jnutbio.2005.06.007
Sun F, Kawasaki E, Akazawa S, Hishikawa Y, Sugahara K, Kamihira S, Koji T and Eguchi K (2005) Apoptosis and its pathway in early post-implantation embryos of diabetic rats. Diabetes Res Clin Pract 67:110-8. https://doi.org/10.1016/j.diabres.2004.06.008
Liu Y and Tang SC (2016) Recent Progress in Stem Cell Therapy for Diabetic Nephropathy. Kidney Dis (Basel) 2:20-7. https://doi.org/10.1159/000441913
Wu Y, Zhang C, Guo R, Wu D, Shi J, Li L, Chu Y, Yuan X and Gao J (2021) Mesenchymal stem cells: an overview of their potential in cell-based therapy for diabetic nephropathy. Stem Cells International 2021. https://doi.org/10.1155/2021/6620811
Ramachandran S, Suguihara C, Drummond S, Chatzistergos K, Klim J, Torres E, Huang J, Hehre D, Rodrigues CO, McNiece IK, Hare JM and Young KC (2015) Bone marrow-derived c-kit+ cells attenuate neonatal hyperoxia-induced lung injury. Cell Transplant 24:85-95. https://doi.org/10.3727/096368913X667736
Fazel S, Cimini M, Chen L, Li S, Angoulvant D, Fedak P, Verma S, Weisel RD, Keating A and Li RK (2006) Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. J Clin Invest 116:1865-77. https://doi.org/10.1172/JCI27019
Loffredo FS, Steinhauser ML, Gannon J and Lee RT (2011) Bone marrow-derived cell therapy stimulates endogenous cardiomyocyte progenitors and promotes cardiac repair. Cell Stem Cell 8:389-98. https://doi.org/10.1016/j.stem.2011.02.002
Huo Y, Mijiti A, Cai R, Gao Z, Aini M, Mijiti A, Wang Z and Qie R (2021) Scutellarin alleviates type 2 diabetes (HFD/low dose STZ)-induced cardiac injury through modulation of oxidative stress, inflammation, apoptosis and fibrosis in mice. Human & Experimental Toxicology 40:S460-S474. https://doi.org/10.1177/09603271211045948
Sheshpari S, Shahnazi M, Ahmadian S, Nouri M, Abbasi MM, Beheshti R, Rahbarghazi R, Honaramooz A and Mahdipour M (2020) Intra-Ovarian Injection of Bone Marrow c-Kit+ Cells Induced Ovarian Rejuvenation in Menopausal Rats. 12:325–335. https://doi.org/10.34172/bi.2021.23499
Rahbarghazi R, Keyhanmanesh R, Rezaie J, Mirershadi F, Heiran H, Saghaei Bagheri H, Saberianpour S, Rezabakhsh A, Delkhosh A, Bagheri Y, Rajabi H and Ahmadi M (2021) c-kit+ cells offer hopes in ameliorating asthmatic pathologies via regulation of miRNA-133 and miRNA-126. Iran J Basic Med Sci 24:369-376. https://doi.org/10.22038/ijbms.2021.49008.11231
Shang G, Gao P, Zhao Z, Chen Q, Jiang T, Zhang N and Li H (2013) 3,5-Diiodo-l-thyronine ameliorates diabetic nephropathy in streptozotocin-induced diabetic rats. Biochim Biophys Acta 1832:674-84. https://doi.org/10.1016/j.bbadis.2013.01.023
Li J, Zelenin S, Aperia A and Aizman O (2006) Low doses of ouabain protect from serum deprivation-triggered apoptosis and stimulate kidney cell proliferation via activation of NF-kappaB. J Am Soc Nephrol 17:1848-57. https://doi.org/10.1681/ASN.2005080894
Ghaffari-Nasab A, Badalzadeh R, Mohaddes G and Alipour MR (2021) Young plasma administration mitigates depression-like behaviours in chronic mild stress-exposed aged rats by attenuating apoptosis in prefrontal cortex. Exp Physiol 106:1621-1630. https://doi.org/10.1113/EP089415
Rangel EB, Gomes SA, Kanashiro-Takeuchi R and Hare JM (2019) Progenitor/Stem Cell Delivery by Suprarenal Aorta Route in Acute Kidney Injury. Cell Transplant 28:1390-1403. https://doi.org/10.1177/0963689719860826
Taghizadeh S, Keyhanmanesh R, Rahbarghazi R, Rezaie J, Delkhosh A, Hassanpour M, Heiran H, Ghaffari-Nasab A and Ahmadi M (2022) Systemic administration of c-Kit(+) cells diminished pulmonary and vascular inflammation in rat model of chronic asthma. BMC Mol Cell Biol 23:11. https://doi.org/10.1186/s12860-022-00410-z
El-Ansary M, Saadi G and Abd El-Hamid SM (2012) Mesenchymal stem cells are a rescue approach for recovery of deteriorating kidney function. Nephrology (Carlton) 17:650-7. https://doi.org/10.1111/j.1440-1797.2012.01622.x
Packham DK, Fraser IR, Kerr PG and Segal KR (2016) Allogeneic Mesenchymal Precursor Cells (MPC) in Diabetic Nephropathy: A Randomized, Placebo-controlled, Dose Escalation Study. EBioMedicine 12:263-269. https://doi.org/10.1016/j.ebiom.2016.09.011
Fransioli J, Bailey B, Gude NA, Cottage CT, Muraski JA, Emmanuel G, Wu W, Alvarez R, Rubio M, Ottolenghi S, Schaefer E and Sussman MA (2008) Evolution of the c-kit-positive cell response to pathological challenge in the myocardium. Stem Cells 26:1315-24. https://doi.org/10.1634/stemcells.2007-0751
Vajravelu BN, Hong KU, Al-Maqtari T, Cao P, Keith MC, Wysoczynski M, Zhao J, Moore JBt and Bolli R (2015) C-Kit Promotes Growth and Migration of Human Cardiac Progenitor Cells via the PI3K-AKT and MEK-ERK Pathways. PLoS One 10:e0140798. https://doi.org/10.1371/journal.pone.0140798
Rahbarghazi R, Keyhanmanesh R, Aslani MR, Hassanpour M and Ahmadi M (2019) Bone marrow mesenchymal stem cells and condition media diminish inflammatory adhesion molecules of pulmonary endothelial cells in an ovalbumin-induced asthmatic rat model. Microvasc Res 121:63-70. https://doi.org/10.1016/j.mvr.2018.10.005
Peired AJ, Sisti A and Romagnani P (2016) Mesenchymal Stem Cell-Based Therapy for Kidney Disease: A Review of Clinical Evidence. Stem Cells Int 2016:4798639. https://doi.org/10.1155/2016/4798639
Eirin A and Lerman LO (2014) Mesenchymal stem cell treatment for chronic renal failure. Stem Cell Res Ther 5:83. https://doi.org/10.1186/scrt472
Lee RH, Seo MJ, Reger RL, Spees JL, Pulin AA, Olson SD and Prockop DJ (2006) Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci U S A 103:17438-43. https://doi.org/ 10.1073/pnas.0608249103
Ezquer FE, Ezquer ME, Parrau DB, Carpio D, Yanez AJ and Conget PA (2008) Systemic administration of multipotent mesenchymal stromal cells reverts hyperglycemia and prevents nephropathy in type 1 diabetic mice. Biol Blood Marrow Transplant 14:631-40. https://doi.org/10.1016/j.bbmt.2008.01.006
Zoja C, Garcia PB, Rota C, Conti S, Gagliardini E, Corna D, Zanchi C, Bigini P, Benigni A, Remuzzi G and Morigi M (2012) Mesenchymal stem cell therapy promotes renal repair by limiting glomerular podocyte and progenitor cell dysfunction in adriamycin-induced nephropathy. Am J Physiol Renal Physiol 303:F1370-81. https://doi.org/10.1152/ajprenal.00057.2012
Magnasco A, Corselli M, Bertelli R, Ibatici A, Peresi M, Gaggero G, Cappiello V, Chiavarina B, Mattioli G, Gusmano R, Ravetti JL, Frassoni F and Ghiggeri GM (2008) Mesenchymal stem cells protective effect in adriamycin model of nephropathy. Cell Transplant 17:1157-67. https://doi.org/10.3727/096368908787236567
Kunter U, Rong S, Djuric Z, Boor P, Muller-Newen G, Yu D and Floege J (2006) Transplanted mesenchymal stem cells accelerate glomerular healing in experimental glomerulonephritis. J Am Soc Nephrol 17:2202-12. https://doi.org/10.1681/ASN.2005080815
Li H, Rong P, Ma X, Nie W, Chen C, Yang C, Zhang J, Dong Q and Wang W (2018) Paracrine effect of mesenchymal stem cell as a novel therapeutic strategy for diabetic nephropathy. Life sciences 215:113-118. https://doi.org/10.1016/j.lfs.2018.11.001
Zhang L, Li K, Liu X, Li D, Luo C, Fu B, Cui S, Zhu F, Zhao RC and Chen X (2013) Repeated systemic administration of human adipose-derived stem cells attenuates overt diabetic nephropathy in rats. Stem Cells Dev 22:3074-86. https://doi.org/10.1089/scd.2013.0142
Gomes SA, Hare JM and Rangel EB (2018) Kidney-Derived c-Kit(+) Cells Possess Regenerative Potential. Stem Cells Transl Med 7:317-324. https://doi.org/10.1002/sctm.17-0232
Rangel EB, Gomes SA, Kanashiro-Takeuchi R, Saltzman RG, Wei C, Ruiz P, Reiser J and Hare JM (2018) Kidney-derived c-kit(+) progenitor/stem cells contribute to podocyte recovery in a model of acute proteinuria. Sci Rep 8:14723. https://doi.org/10.1038/s41598-018-33082-x
Abdi R, Fiorina P, Adra CN, Atkinson M and Sayegh MH (2008) Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes. Diabetes 57:1759-67. https://doi.org/10.2337/db08-0180
Lv SS, Liu G, Wang JP, Wang WW, Cheng J, Sun AL, Liu HY, Nie HB, Su MR and Guan GJ (2013) Mesenchymal stem cells transplantation ameliorates glomerular injury in streptozotocin-induced diabetic nephropathy in rats via inhibiting macrophage infiltration. Int Immunopharmacol 17:275-82. https://doi.org/10.1016/j.intimp.2013.05.031
Ezquer F, Giraud-Billoud M, Carpio D, Cabezas F, Conget P and Ezquer M (2015) Proregenerative Microenvironment Triggered by Donor Mesenchymal Stem Cells Preserves Renal Function and Structure in Mice with Severe Diabetes Mellitus. Biomed Res Int 2015:164703. https://doi.org/10.1155/2015/164703
Li Y, Liu J, Liao G, Zhang J, Chen Y, Li L, Li L, Liu F, Chen B, Guo G, Wang C, Yang L, Cheng J and Lu Y (2018) Early intervention with mesenchymal stem cells prevents nephropathy in diabetic rats by ameliorating the inflammatory microenvironment. Int J Mol Med 41:2629-2639. https://doi.org/10.3892/ijmm.2018.3501
Corti S, Nizzardo M, Nardini M, Donadoni C, Salani S, Simone C, Falcone M, Riboldi G, Govoni A, Bresolin N and Comi GP (2010) Systemic transplantation of c-kit+ cells exerts a therapeutic effect in a model of amyotrophic lateral sclerosis. Hum Mol Genet 19:3782-96. https://doi.org/10.1093/hmg/ddq293
Park JH, Hwang I, Hwang SH, Han H and Ha H (2012) Human umbilical cord blood-derived mesenchymal stem cells prevent diabetic renal injury through paracrine action. Diabetes research and clinical practice 98:465-473. https://doi.org/10.1016/j.diabres.2012.09.034
Tolar J, Le Blanc K, Keating A and Blazar BR (2010) Concise review: hitting the right spot with mesenchymal stromal cells. Stem Cells 28:1446-55. https://doi.org/10.1002/stem.459
Liu D, Zheng W, Pan S and Liu Z (2020) Concise review: current trends on applications of stem cells in diabetic nephropathy. Cell Death Dis 11:1000. https://doi.org/10.1038/s41419-020-03206-1
Kumar D, Zimpelmann J, Robertson S and Burns KD (2004) Tubular and interstitial cell apoptosis in the streptozotocin-diabetic rat kidney. Nephron experimental nephrology 96:e77-e88. https://doi.org/ 10.1159/000076749
Kumar D, Robertson S and Burns KD (2004) Evidence of apoptosis in human diabetic kidney. Mol Cell Biochem 259:67-70. https://doi.org/10.1023/b:mcbi.0000021346.03260.7e
Shih YC, Lee PY, Cheng H, Tsai CH, Ma H and Tarng DC (2013) Adipose-derived stem cells exhibit antioxidative and antiapoptotic properties to rescue ischemic acute kidney injury in rats. Plast Reconstr Surg 132:940e-951e. https://doi.org/10.1097/PRS.0b013e3182a806ce
Humphreys BD, Cantaluppi V, Portilla D, Singbartl K, Yang L, Rosner MH, Kellum JA, Ronco C and Acute Dialysis Quality Initiative XWG (2016) Targeting Endogenous Repair Pathways after AKI. J Am Soc Nephrol 27:990-8. https://doi.org/10.1681/ASN.2015030286
Rowart P, Erpicum P, Detry O, Weekers L, Gregoire C, Lechanteur C, Briquet A, Beguin Y, Krzesinski JM and Jouret F (2015) Mesenchymal Stromal Cell Therapy in Ischemia/Reperfusion Injury. J Immunol Res 2015:602597. https://doi.org/10.1155/2015/602597
Fleig SV and Humphreys BD (2014) Rationale of mesenchymal stem cell therapy in kidney injury. Nephron Clin Pract 127:75-80. https://doi.org/10.1159/000363680
Abdel Aziz MT, Wassef MAA, Ahmed HH, Rashed L, Mahfouz S, Aly MI, Hussein RE and Abdelaziz M (2014) The role of bone marrow derived-mesenchymal stem cells in attenuation of kidney function in rats with diabetic nephropathy. Diabetology & metabolic syndrome 6:1-10. https://doi.org/10.1186/1758-5996-6-34
Ni W, Fang Y, Xie L, Liu X, Shan W, Zeng R, Liu J and Liu X (2015) Adipose-Derived Mesenchymal Stem Cells Transplantation Alleviates Renal Injury in Streptozotocin-Induced Diabetic Nephropathy. J Histochem Cytochem 63:842-53. https://doi.org/10.1369/0022155415599039
Bianchi F, Sala E, Donadei C, Capelli I and La Manna G (2014) Potential advantages of acute kidney injury management by mesenchymal stem cells. World J Stem Cells 6:644-50. https://doi.org/10.4252/wjsc.v6.i5.644
Ayach BB, Yoshimitsu M, Dawood F, Sun M, Arab S, Chen M, Higuchi K, Siatskas C, Lee P, Lim H, Zhang J, Cukerman E, Stanford WL, Medin JA and Liu PP (2006) Stem cell factor receptor induces progenitor and natural killer cell-mediated cardiac survival and repair after myocardial infarction. Proc Natl Acad Sci U S A 103:2304-9. https://doi.org/10.1073/pnas.0510997103
Dhandapani KM, Wade FM, Wakade C, Mahesh VB and Brann DW (2005) Neuroprotection by stem cell factor in rat cortical neurons involves AKT and NFκB. Journal of neurochemistry 95:9-19. https://doi.org/10.1111/j.1471-4159.2005.03319.x
Uemura R, Xu M, Ahmad N and Ashraf M (2006) Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circulation research 98:1414-1421. https://doi.org/10.1161/01.RES.0000225952.61196.39
Xu M, Uemura R, Dai Y, Wang Y, Pasha Z and Ashraf M (2007) In vitro and in vivo effects of bone marrow stem cells on cardiac structure and function. J Mol Cell Cardiol 42:441-8. https://doi.org/10.1016/j.yjmcc.2006.10.009
Serve H, Hsu Y-C and Besmer P (1994) Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells. Journal of Biological Chemistry 269:6026-6030. https://doi.org/10.1016/S0021-9258(17)37564-6
Blume-Jensen P, Janknecht R and Hunter T (1998) The kit receptor promotes cell survival via activation of PI 3-kinase and subsequent Akt-mediated phosphorylation of Bad on Ser136. Curr Biol 8:779-82. https://doi.org/10.1016/s0960-9822(98)70302-1
Ying C, Wang S, Lu Y, Chen L, Mao Y, Ling H, Cheng X and Zhou X (2019) Glucose fluctuation increased mesangial cell apoptosis related to AKT signal pathway. Arch Med Sci 15:730-737. https://doi.org/10.5114/aoms.2019.84739
Qin J, Wang L-l, Liu Z-y, Zou Y-l, Fei Y-j and Liu Z-x (2018) Ezetimibe protects endothelial cells against oxidative stress through Akt/GSK-3β pathway. Current medical science 38:398-404. https://doi.org/10.1007/s11596-018-1892-3
Qian X, He L, Hao M, Li Y, Li X, Liu Y, Jiang H, Xu L, Li C and Wu W (2021) YAP mediates the interaction between the Hippo and PI3K/Akt pathways in mesangial cell proliferation in diabetic nephropathy. Acta Diabetologica 58:47-62. https://doi.org/10.1007/s00592-020-01582-w
Rai U, Kosuru R, Prakash S, Tiwari V and Singh S (2019) Tetramethylpyrazine alleviates diabetic nephropathy through the activation of Akt signalling pathway in rats. European Journal of Pharmacology 865:172763. https://doi.org/10.1016/j.ejphar.2019.172763
Rönnstrand L (2004) Signal transduction via the stem cell factor receptor/c-Kit. Cellular and Molecular Life Sciences CMLS 61:2535-2548. https://doi.org/10.1007/s00018-004-4189-6
Gude N, Muraski J, Rubio M, Kajstura J, Schaefer E, Anversa P and Sussman MA (2006) Akt promotes increased cardiomyocyte cycling and expansion of the cardiac progenitor cell population. Circ Res 99:381-8. https://doi.org/10.1161/01.RES.0000236754.21499.1c
Jia X, Xie X, Feng G, Lű H, Zhao Q, Che Y, Zheng Y, Han Z, Xu Y and Li Z (2012) Bone marrow-derived cells can acquire renal stem cells properties and ameliorate ischemia-reperfusion induced acute renal injury. BMC nephrology 13:1-9. https://doi.org/10.1186/1471-2369-13-105

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Bone marrow-derived c-kit positive stem cell administration protects against diabetes-induced nephropathy in a rat model by reversing PI3K/AKT/GSK-3β pathway and inhibiting cell apoptosis

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