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Adipose Tissue-Derived Stem Cells Reduce Acute and Chronic Kidney Damage in Mice.

Burgos-Silva M, Semedo-Kuriki P, Donizetti-Oliveira C, Costa PB, Cenedeze MA, Hiyane MI, Pacheco-Silva A, Câmara NO - PLoS ONE (2015)

Bottom Line: Long-term analyses, 4 weeks after FA, indicated that AdSC treatment reduced kidney fibrosis and chronic inflammation.These were demonstrated by reduced interstitial collagen deposition and tissue chemokine and cytokine expression.Thus, we concluded that AdSC treatment played a protective role in the framework of nephrotoxic injury via modulation of inflammation and cell cycle regulation, resulting in reduced kidney damage and functional improvement, inhibiting organ fibrosis and providing long-term immune regulation.

View Article: PubMed Central - PubMed

Affiliation: Nephrology Division, Federal University of São Paulo, São Paulo, São Paulo, Brazil.

ABSTRACT
Acute and chronic kidney injuries (AKI and CKI) constitute syndromes responsible for a large part of renal failures, and are today still associated with high mortality rates. Given the lack of more effective therapies, there has been intense focus on the use stem cells for organ protective and regenerative effects. Mesenchymal stem cells (MSCs) have shown great potential in the treatment of various diseases of immune character, although there is still debate on its mechanism of action. Thus, for a greater understanding of the role of MSCs, we evaluated the effect of adipose tissue-derived stem cells (AdSCs) in an experimental model of nephrotoxicity induced by folic acid (FA) in FVB mice. AdSC-treated animals displayed kidney functional improvement 24h after therapy, represented by reduced serum urea after FA. These data correlated with cell cycle regulation and immune response modulation via reduced chemokine expression and reduced neutrophil infiltrate. Long-term analyses, 4 weeks after FA, indicated that AdSC treatment reduced kidney fibrosis and chronic inflammation. These were demonstrated by reduced interstitial collagen deposition and tissue chemokine and cytokine expression. Thus, we concluded that AdSC treatment played a protective role in the framework of nephrotoxic injury via modulation of inflammation and cell cycle regulation, resulting in reduced kidney damage and functional improvement, inhibiting organ fibrosis and providing long-term immune regulation.

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Folic Acid-induced chronic kidney injury.Mice were submitted to folic acid-induced kidney injury (FA) or sodium bicarbonate (Bic) vehicle treatment and after 24 h, received adipose tissue-derived stem cells (AdSC). Kidney tissue and serum samples were extracted 4 weeks after FA for kidney function and protein expression analyses; control (Ctr) mice received no treatment, (Bic) mice received vehicle only (sodium bicarbonate, 0.15 M). (A) Urea biochemistry essays showed no significant difference of long term renal functional between groups (n = 2–7 for each group) (B,C) Kidney sections were viewed under both bright-field (a-e) and polarized light (f-j) microscopy. AdSC-treated mice kidneys displayed reduced deposit of tissue collagen in comparison to FA mice (n = 3–5 for each group) (original magnification: 20x). (D) Bioplex essays show stem cell-treated mice develop ameliorated chronic kidney inflammation (n = 3 for each group). FA-treated mice expressed higher levels of interferon-gamma (IFN-γ) vs. control mice, while in AdSC-treated mice, IFN-γ and eotaxin expression was shown to be reduced in kidney tissue vs. the latter. A tendency towards lower interleukine-2 (IL-2) and MIP-1α expression was also observed for these animals (n = 2–6 for each group). Immunohistochemistry values are expressed as the percentage of area of polarized light ± s.d. Scale bar, 50 μm. Bioplex values are expressed as (μg/mL) ± s.d. *P<0.05, **P<0.01 ***P<0.001
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pone.0142183.g003: Folic Acid-induced chronic kidney injury.Mice were submitted to folic acid-induced kidney injury (FA) or sodium bicarbonate (Bic) vehicle treatment and after 24 h, received adipose tissue-derived stem cells (AdSC). Kidney tissue and serum samples were extracted 4 weeks after FA for kidney function and protein expression analyses; control (Ctr) mice received no treatment, (Bic) mice received vehicle only (sodium bicarbonate, 0.15 M). (A) Urea biochemistry essays showed no significant difference of long term renal functional between groups (n = 2–7 for each group) (B,C) Kidney sections were viewed under both bright-field (a-e) and polarized light (f-j) microscopy. AdSC-treated mice kidneys displayed reduced deposit of tissue collagen in comparison to FA mice (n = 3–5 for each group) (original magnification: 20x). (D) Bioplex essays show stem cell-treated mice develop ameliorated chronic kidney inflammation (n = 3 for each group). FA-treated mice expressed higher levels of interferon-gamma (IFN-γ) vs. control mice, while in AdSC-treated mice, IFN-γ and eotaxin expression was shown to be reduced in kidney tissue vs. the latter. A tendency towards lower interleukine-2 (IL-2) and MIP-1α expression was also observed for these animals (n = 2–6 for each group). Immunohistochemistry values are expressed as the percentage of area of polarized light ± s.d. Scale bar, 50 μm. Bioplex values are expressed as (μg/mL) ± s.d. *P<0.05, **P<0.01 ***P<0.001

Mentions: In the clinical setting, studies have correlated a higher incidence of CKI amongst patients with AKI. In accordance, researches demonstrate that FA-induced AKI is able to induce kidney fibrosis, reflecting clinical observations. Therefore, we next aimed towards characterizing folic acid-induced progression of CKI and the consequences of AdSC therapy in this injury. In order to evaluate kidney fibrogenesis, picrosirius red staining of collagen fibers was analyzed through polarized light microscopy and quantified. Analysis showed a rise in tissue fibrosis 4 weeks after folic acid-induced kidney injury. In contrast, this profile was significantly reduced in animals that received AdSC therapy 24 h after FA, demonstrating that stem cells were efficient in preventing collagen deposition in kidney tissue, reducing tissue fibrosis at long term (Fig 3A and 3B). In order to better elucidate the long-term effects of AdSC in kidneys, we also performed tissue protein expression assays in the chronic model. Bioplex analyses showed elevated expression of INF-γ in kidneys which puts to evidence the chronic character of tissue damage. Moreover, AdSC-treated mice displayed significant reduction in interferon gamma (IFN-γ) and eotaxin levels (Fig 3C). These data confirm that AdSC therapy was also capable of halting the persisting inflammatory process even 4 weeks after initial kidney damage.


Adipose Tissue-Derived Stem Cells Reduce Acute and Chronic Kidney Damage in Mice.

Burgos-Silva M, Semedo-Kuriki P, Donizetti-Oliveira C, Costa PB, Cenedeze MA, Hiyane MI, Pacheco-Silva A, Câmara NO - PLoS ONE (2015)

Folic Acid-induced chronic kidney injury.Mice were submitted to folic acid-induced kidney injury (FA) or sodium bicarbonate (Bic) vehicle treatment and after 24 h, received adipose tissue-derived stem cells (AdSC). Kidney tissue and serum samples were extracted 4 weeks after FA for kidney function and protein expression analyses; control (Ctr) mice received no treatment, (Bic) mice received vehicle only (sodium bicarbonate, 0.15 M). (A) Urea biochemistry essays showed no significant difference of long term renal functional between groups (n = 2–7 for each group) (B,C) Kidney sections were viewed under both bright-field (a-e) and polarized light (f-j) microscopy. AdSC-treated mice kidneys displayed reduced deposit of tissue collagen in comparison to FA mice (n = 3–5 for each group) (original magnification: 20x). (D) Bioplex essays show stem cell-treated mice develop ameliorated chronic kidney inflammation (n = 3 for each group). FA-treated mice expressed higher levels of interferon-gamma (IFN-γ) vs. control mice, while in AdSC-treated mice, IFN-γ and eotaxin expression was shown to be reduced in kidney tissue vs. the latter. A tendency towards lower interleukine-2 (IL-2) and MIP-1α expression was also observed for these animals (n = 2–6 for each group). Immunohistochemistry values are expressed as the percentage of area of polarized light ± s.d. Scale bar, 50 μm. Bioplex values are expressed as (μg/mL) ± s.d. *P<0.05, **P<0.01 ***P<0.001
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4643882&req=5

pone.0142183.g003: Folic Acid-induced chronic kidney injury.Mice were submitted to folic acid-induced kidney injury (FA) or sodium bicarbonate (Bic) vehicle treatment and after 24 h, received adipose tissue-derived stem cells (AdSC). Kidney tissue and serum samples were extracted 4 weeks after FA for kidney function and protein expression analyses; control (Ctr) mice received no treatment, (Bic) mice received vehicle only (sodium bicarbonate, 0.15 M). (A) Urea biochemistry essays showed no significant difference of long term renal functional between groups (n = 2–7 for each group) (B,C) Kidney sections were viewed under both bright-field (a-e) and polarized light (f-j) microscopy. AdSC-treated mice kidneys displayed reduced deposit of tissue collagen in comparison to FA mice (n = 3–5 for each group) (original magnification: 20x). (D) Bioplex essays show stem cell-treated mice develop ameliorated chronic kidney inflammation (n = 3 for each group). FA-treated mice expressed higher levels of interferon-gamma (IFN-γ) vs. control mice, while in AdSC-treated mice, IFN-γ and eotaxin expression was shown to be reduced in kidney tissue vs. the latter. A tendency towards lower interleukine-2 (IL-2) and MIP-1α expression was also observed for these animals (n = 2–6 for each group). Immunohistochemistry values are expressed as the percentage of area of polarized light ± s.d. Scale bar, 50 μm. Bioplex values are expressed as (μg/mL) ± s.d. *P<0.05, **P<0.01 ***P<0.001
Mentions: In the clinical setting, studies have correlated a higher incidence of CKI amongst patients with AKI. In accordance, researches demonstrate that FA-induced AKI is able to induce kidney fibrosis, reflecting clinical observations. Therefore, we next aimed towards characterizing folic acid-induced progression of CKI and the consequences of AdSC therapy in this injury. In order to evaluate kidney fibrogenesis, picrosirius red staining of collagen fibers was analyzed through polarized light microscopy and quantified. Analysis showed a rise in tissue fibrosis 4 weeks after folic acid-induced kidney injury. In contrast, this profile was significantly reduced in animals that received AdSC therapy 24 h after FA, demonstrating that stem cells were efficient in preventing collagen deposition in kidney tissue, reducing tissue fibrosis at long term (Fig 3A and 3B). In order to better elucidate the long-term effects of AdSC in kidneys, we also performed tissue protein expression assays in the chronic model. Bioplex analyses showed elevated expression of INF-γ in kidneys which puts to evidence the chronic character of tissue damage. Moreover, AdSC-treated mice displayed significant reduction in interferon gamma (IFN-γ) and eotaxin levels (Fig 3C). These data confirm that AdSC therapy was also capable of halting the persisting inflammatory process even 4 weeks after initial kidney damage.

Bottom Line: Long-term analyses, 4 weeks after FA, indicated that AdSC treatment reduced kidney fibrosis and chronic inflammation.These were demonstrated by reduced interstitial collagen deposition and tissue chemokine and cytokine expression.Thus, we concluded that AdSC treatment played a protective role in the framework of nephrotoxic injury via modulation of inflammation and cell cycle regulation, resulting in reduced kidney damage and functional improvement, inhibiting organ fibrosis and providing long-term immune regulation.

View Article: PubMed Central - PubMed

Affiliation: Nephrology Division, Federal University of São Paulo, São Paulo, São Paulo, Brazil.

ABSTRACT
Acute and chronic kidney injuries (AKI and CKI) constitute syndromes responsible for a large part of renal failures, and are today still associated with high mortality rates. Given the lack of more effective therapies, there has been intense focus on the use stem cells for organ protective and regenerative effects. Mesenchymal stem cells (MSCs) have shown great potential in the treatment of various diseases of immune character, although there is still debate on its mechanism of action. Thus, for a greater understanding of the role of MSCs, we evaluated the effect of adipose tissue-derived stem cells (AdSCs) in an experimental model of nephrotoxicity induced by folic acid (FA) in FVB mice. AdSC-treated animals displayed kidney functional improvement 24h after therapy, represented by reduced serum urea after FA. These data correlated with cell cycle regulation and immune response modulation via reduced chemokine expression and reduced neutrophil infiltrate. Long-term analyses, 4 weeks after FA, indicated that AdSC treatment reduced kidney fibrosis and chronic inflammation. These were demonstrated by reduced interstitial collagen deposition and tissue chemokine and cytokine expression. Thus, we concluded that AdSC treatment played a protective role in the framework of nephrotoxic injury via modulation of inflammation and cell cycle regulation, resulting in reduced kidney damage and functional improvement, inhibiting organ fibrosis and providing long-term immune regulation.

Show MeSH
Related in: MedlinePlus