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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 acute 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 24 h after AdSC therapy 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 revealed that AdSC treatment conferred protection against acute kidney dysfunction as seen through lower serum urea accumulation (n = 2–6 for each group); (B-D) Immunohistochemistry of kidney tissue. Semi-quantification of proliferating cell nuclear antigen (PCNA) staining demonstrates normalized cell proliferation rates after AdSC treatment vs. FA mice (B,C) (n = 2–5 for each group). Immunohistochemistry also showed reduced neutrophil infiltrate seen through myeloperoxidase (MPO) staining after AdSC treatment vs. FA mice (B,D) (n = 2–3 for each group). Arrows indicate positive MPO staining (original magnification: 20x). (E) Kidney bioplex essays showed reduced inflammatory profiles in stem cell treated mice, (n = 3 for each group). Neutrophil chemoattractant protein chemokine (C-X-C motif) ligand 1 (CXCL1), and macrophage inflammatory protein 1 alpha (MIP-1α) levels n were increased in AdSC-treated mice. In parallel, granulocyte macrophage colony stimulating factor (GM-CSF) and CXCL-1 expression was reduced in the AdSC-treated group. A tendency towards lower monocyte chemoattractive protein-1 (MCP-1) and interleukine 6 (IL-6) expression was also observed for these animals (n = 2–3 for each group). Serum urea levels are expressed as (mg/dL ± s.d.). Immunohistochemistry values are expressed as the percentage of area positive for PCNA ± s.d. or the number of cells positively stained for MPO per mm2 ± s.d.). Scale bar, 25 μm. Bioplex values are expressed as (pg/mL) ± s.d. *P<0.05, **P<0.01 ***P<0.001
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pone.0142183.g002: Folic Acid-induced acute 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 24 h after AdSC therapy 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 revealed that AdSC treatment conferred protection against acute kidney dysfunction as seen through lower serum urea accumulation (n = 2–6 for each group); (B-D) Immunohistochemistry of kidney tissue. Semi-quantification of proliferating cell nuclear antigen (PCNA) staining demonstrates normalized cell proliferation rates after AdSC treatment vs. FA mice (B,C) (n = 2–5 for each group). Immunohistochemistry also showed reduced neutrophil infiltrate seen through myeloperoxidase (MPO) staining after AdSC treatment vs. FA mice (B,D) (n = 2–3 for each group). Arrows indicate positive MPO staining (original magnification: 20x). (E) Kidney bioplex essays showed reduced inflammatory profiles in stem cell treated mice, (n = 3 for each group). Neutrophil chemoattractant protein chemokine (C-X-C motif) ligand 1 (CXCL1), and macrophage inflammatory protein 1 alpha (MIP-1α) levels n were increased in AdSC-treated mice. In parallel, granulocyte macrophage colony stimulating factor (GM-CSF) and CXCL-1 expression was reduced in the AdSC-treated group. A tendency towards lower monocyte chemoattractive protein-1 (MCP-1) and interleukine 6 (IL-6) expression was also observed for these animals (n = 2–3 for each group). Serum urea levels are expressed as (mg/dL ± s.d.). Immunohistochemistry values are expressed as the percentage of area positive for PCNA ± s.d. or the number of cells positively stained for MPO per mm2 ± s.d.). Scale bar, 25 μm. Bioplex values are expressed as (pg/mL) ± s.d. *P<0.05, **P<0.01 ***P<0.001

Mentions: In order to evaluate the effect of AdSC treatment on a mouse model of nephrotoxic kidney injury, our studied initially focused on the acute effects of this therapy on FA-induced AKI. For so, FVB mice received 200 mg/kg FA (i.p.) and after 24 h were submitted to singenic AdSC therapy. Initial essays indicated that FA significantly impaired kidney function, inducing the accumulation of serum urea. In contrast, stem cells protected kidneys against AKI, as seen through a reduction in serum urea levels 48 h after FA (Fig 2A).


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 acute 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 24 h after AdSC therapy 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 revealed that AdSC treatment conferred protection against acute kidney dysfunction as seen through lower serum urea accumulation (n = 2–6 for each group); (B-D) Immunohistochemistry of kidney tissue. Semi-quantification of proliferating cell nuclear antigen (PCNA) staining demonstrates normalized cell proliferation rates after AdSC treatment vs. FA mice (B,C) (n = 2–5 for each group). Immunohistochemistry also showed reduced neutrophil infiltrate seen through myeloperoxidase (MPO) staining after AdSC treatment vs. FA mice (B,D) (n = 2–3 for each group). Arrows indicate positive MPO staining (original magnification: 20x). (E) Kidney bioplex essays showed reduced inflammatory profiles in stem cell treated mice, (n = 3 for each group). Neutrophil chemoattractant protein chemokine (C-X-C motif) ligand 1 (CXCL1), and macrophage inflammatory protein 1 alpha (MIP-1α) levels n were increased in AdSC-treated mice. In parallel, granulocyte macrophage colony stimulating factor (GM-CSF) and CXCL-1 expression was reduced in the AdSC-treated group. A tendency towards lower monocyte chemoattractive protein-1 (MCP-1) and interleukine 6 (IL-6) expression was also observed for these animals (n = 2–3 for each group). Serum urea levels are expressed as (mg/dL ± s.d.). Immunohistochemistry values are expressed as the percentage of area positive for PCNA ± s.d. or the number of cells positively stained for MPO per mm2 ± s.d.). Scale bar, 25 μm. Bioplex values are expressed as (pg/mL) ± s.d. *P<0.05, **P<0.01 ***P<0.001
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pone.0142183.g002: Folic Acid-induced acute 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 24 h after AdSC therapy 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 revealed that AdSC treatment conferred protection against acute kidney dysfunction as seen through lower serum urea accumulation (n = 2–6 for each group); (B-D) Immunohistochemistry of kidney tissue. Semi-quantification of proliferating cell nuclear antigen (PCNA) staining demonstrates normalized cell proliferation rates after AdSC treatment vs. FA mice (B,C) (n = 2–5 for each group). Immunohistochemistry also showed reduced neutrophil infiltrate seen through myeloperoxidase (MPO) staining after AdSC treatment vs. FA mice (B,D) (n = 2–3 for each group). Arrows indicate positive MPO staining (original magnification: 20x). (E) Kidney bioplex essays showed reduced inflammatory profiles in stem cell treated mice, (n = 3 for each group). Neutrophil chemoattractant protein chemokine (C-X-C motif) ligand 1 (CXCL1), and macrophage inflammatory protein 1 alpha (MIP-1α) levels n were increased in AdSC-treated mice. In parallel, granulocyte macrophage colony stimulating factor (GM-CSF) and CXCL-1 expression was reduced in the AdSC-treated group. A tendency towards lower monocyte chemoattractive protein-1 (MCP-1) and interleukine 6 (IL-6) expression was also observed for these animals (n = 2–3 for each group). Serum urea levels are expressed as (mg/dL ± s.d.). Immunohistochemistry values are expressed as the percentage of area positive for PCNA ± s.d. or the number of cells positively stained for MPO per mm2 ± s.d.). Scale bar, 25 μm. Bioplex values are expressed as (pg/mL) ± s.d. *P<0.05, **P<0.01 ***P<0.001
Mentions: In order to evaluate the effect of AdSC treatment on a mouse model of nephrotoxic kidney injury, our studied initially focused on the acute effects of this therapy on FA-induced AKI. For so, FVB mice received 200 mg/kg FA (i.p.) and after 24 h were submitted to singenic AdSC therapy. Initial essays indicated that FA significantly impaired kidney function, inducing the accumulation of serum urea. In contrast, stem cells protected kidneys against AKI, as seen through a reduction in serum urea levels 48 h after FA (Fig 2A).

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