Mesenchymal Stromal Cells Prevent Renal Fibrosis in a Rat Model of Unilateral Ureteral Obstruction by Suppressing the Renin-Angiotensin System via HuR

Gregorini, Marilena; Corradetti, Valeria; Rocca, Chiara; Pattonieri, Eleonora Francesca; Valsania, Teresa; Milanesi, Samantha; Serpieri, Nicoletta; Bedino, Giulia; Esposito, Pasquale; Libetta, Carmelo; Avanzini, Maria Antonietta; Mantelli, Melissa; Ingo, Daniela; Peressini, Sabrina; Albertini, Riccardo; Canton, Antonio Dal; Rampino, Teresa

doi:10.1371/journal.pone.0148542

Cited by 30 publications

(29 citation statements)

References 64 publications

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“…Several studies have demonstrated that MSCs can protect against acute and chronic renal injury (1,8,28), and, while the mechanism of MSC-induced renal protection remains unknown, recent studies suggest that a significant component of MSC's protective and reparative function resides in their paracrine activity. MSCs can secrete a number of growth factors and cytokines that are important for angiogenesis and cytoprotection and have been demonstrated to prevent tubulointerstitial fibrosis during chronic unilateral ureteral obstruction (UUO) (2,5,9).…”

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confidence: 99%

Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production

Matsui

Babitz

Rhee

et al. 2017

American Journal of Physiology-Renal Physiology

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STAT3 is a transcription factor implicated in renal fibrotic injury, but the role of STAT3 in mesenchymal stem cell (MSC)-induced renoprotection during renal fibrosis remains unknown. We hypothesized that MSCs protect against obstruction-induced renal fibrosis by downregulating STAT3 activation and STAT3-induced matrix metalloproteinase-9 (MMP-9) expression. Male Sprague-Dawley rats underwent renal arterial injection of vehicle or MSCs (1 × 10/rat) immediately before sham operation or induction of unilateral ureteral obstruction (UUO). The kidneys were harvested after 4 wk and analyzed for collagen I and III gene expression, collagen deposition (Masson's trichrome), fibronectin, α-smooth muscle actin, active STAT3 (p-STAT3), MMP-9, and tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) expression. In a separate arm, the STAT3 inhibitor S3I-201 (10 mg/kg) vs. vehicle was administered to rats intraperitoneally just after induction of UUO and daily for 14 days thereafter. The kidneys were harvested after 2 wk and analyzed for p-STAT3 and MMP-9 expression, and collagen and fibronectin deposition. Renal obstruction induced a significant increase in collagen, fibronectin, α-SMA, p-STAT3, MMP-9, and TIMP-1 expression while exogenously administered MSCs significantly reduced these indicators of obstruction-induced renal fibrosis. STAT3 inhibition with S3I-201 significantly reduced obstruction-induced MMP-9 expression and tubulointerstitial fibrosis. These results demonstrate that MSCs protect against obstruction-induced renal fibrosis, in part, by decreasing STAT3 activation and STAT3-dependent MMP-9 production.

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confidence: 99%

Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production

Matsui

Babitz

Rhee

et al. 2017

American Journal of Physiology-Renal Physiology

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“…MSC were isolated from bone marrow of EGFP transgenic SD rats, expanded in vitro and used at P2/P3 as previously described .…”

Section: Methodsmentioning

confidence: 99%

“…EGFP‐rat MSC, hereafter referred to as MSC, were characterized for plastic adhesion, morphology, antigen surface expression of CD49e, CD90 and CD29 and the absence of CD45 and CD11b (all antibodies were purchased from BioLegend, San Diego, CA, USA) performed with a Navios flow cytometer (Beckman Coulter, Milan, Italy) and differentiation capacity .…”

Section: Methodsmentioning

confidence: 99%

Perfusion of isolated rat kidney with Mesenchymal Stromal Cells/Extracellular Vesicles prevents ischaemic injury

Gregorini

Corradetti

Pattonieri

et al. 2017

J Cellular Molecular Medi

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Kidney donation after circulatory death (DCD) is a less than ideal option to meet organ shortages. Hypothermic machine perfusion (HMP) with Belzer solution (BS) improves the viability of DCD kidneys, although the graft clinical course remains critical. Mesenchymal stromal cells (MSC) promote tissue repair by releasing extracellular vesicles (EV). We evaluated whether delivering MSC‐/MSC‐derived EV during HMP protects rat DCD kidneys from ischaemic injury and investigated the underlying pathogenic mechanisms. Warm ischaemic isolated kidneys were cold‐perfused (4 hrs) with BS, BS supplemented with MSC or EV. Renal damage was evaluated by histology and renal gene expression by microarray analysis, RT‐PCR. Malondialdehyde, lactate, LDH, glucose and pyruvate were measured in the effluent fluid. MSC‐/EV‐treated kidneys showed significantly less global ischaemic damage. In the MSC/EV groups, there was up‐regulation of three genes encoding enzymes known to improve cell energy metabolism and three genes encoding proteins involved in ion membrane transport. In the effluent fluid, lactate, LDH, MDA and glucose were significantly lower and pyruvate higher in MSC/EV kidneys as compared with BS, suggesting the larger use of energy substrates by MSC/EV kidneys. The addition of MSC/EV to BS during HMP protects the kidney from ischaemic injury by preserving the enzymatic machinery essential for cell viability and protects the kidney from reperfusion damage.

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“…In addition, IL-10 also appears to have an effect on profibrotic signaling pathways that are unique to the kidney, specifically that mesenchymal stromal cell-released IL-10 inhibited RAAS signaling and thereby reduced tubular scarring after unilateral ureteral obstruction (UUO). 93 As in the heart, the molecular mechanism behind this effect appeared to be a decrease in inflammatory cytokine mRNA due to HuR transcription inhibition. Similarly, our laboratory has shown that exogenous IL-10 administration post-UUO attenuates tubulointerstitial fibrosis and is additionally associated with upregulated HMW-HA, similar to the effects seen with IL-10 in the skin.…”

Section: Renal Fibrosismentioning

confidence: 99%

The Role of the Anti-Inflammatory Cytokine Interleukin-10 in Tissue Fibrosis

Steen

Wang

Balaji

et al. 2020

Advances in Wound Care

264

158

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Significance: Fibrosis is the endpoint of chronic disease in multiple organs, including the skin, heart, lungs, intestine, liver, and kidneys. Pathologic accumulation of fibrotic tissue results in a loss of structural integrity and function, with resultant increases in morbidity and mortality. Understanding the pathways governing fibrosis and identifying therapeutic targets within those pathways is necessary to develop novel antifibrotic therapies for fibrotic disease. Recent Advances: Given the connection between inflammation and fibrogenesis, Interleukin-10 (IL-10) has been a focus of potential antifibrotic therapies because of its well-known role as an anti-inflammatory mediator. Despite the apparent dissimilarity of diseases associated with fibrotic progression, pathways involving IL-10 appear to be a conserved molecular theme. More recently, many groups have worked to develop novel delivery tools for recombinant IL-10, such as hydrogels, and cellbased therapies, such as ex vivo activated macrophages, to directly or indirectly modulate IL-10 signaling. Critical Issues: Some efforts in this area, however, have been stymied by IL-10's pleiotropic and sometimes conflicting effects. A deeper, contextual understanding of IL-10 signaling and its interaction with effector cells, particularly immune cells, will be critical to future studies in the field. Future Directions: IL-10 is clearly a gatekeeper of fibrotic/antifibrotic signaling. The development of novel therapeutics and cell-based therapies that capitalize on targets within the IL-10 signaling pathway could have far-reaching implications for patients suffering from the consequences of organ fibrosis.

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Mesenchymal Stromal Cells Prevent Renal Fibrosis in a Rat Model of Unilateral Ureteral Obstruction by Suppressing the Renin-Angiotensin System via HuR

Cited by 30 publications

References 64 publications

Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production

Mesenchymal stem cells protect against obstruction-induced renal fibrosis by decreasing STAT3 activation and STAT3-dependent MMP-9 production

Perfusion of isolated rat kidney with Mesenchymal Stromal Cells/Extracellular Vesicles prevents ischaemic injury

The Role of the Anti-Inflammatory Cytokine Interleukin-10 in Tissue Fibrosis

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