Renal Inflammation and Fibrosis: A Double-edged Sword

Black, Laurence M.; Lever, Jeremie M.; Agarwal, Anupam

doi:10.1369/0022155419852932

Cited by 100 publications

(60 citation statements)

References 202 publications

(284 reference statements)

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“…A similar trend was also observed in the expression of the ltbp1 gene which encodes for the LTBP1 protein, involved in the activation of TGFβ-1. Of note, these data suggest a possible mechanism of action of MSC-EVs in the regulation of TGFβ-1, which itself is a key stone in the progression of inflammation and fibrosis (Wang et al, 2008;Black et al, 2019). miRNAs are non-coding RNA molecules, that function as post-transcriptional regulators, blocking target mRNAs.…”

Section: Discussionmentioning

confidence: 99%

“…The activation of inflammatory, fibrotic, and reparative processes occur simultaneously to promote regeneration and repair, following an insult. An increase in the infiltration of inflammatory and pro-fibrotic cells can impair tissue regeneration and lead to fibrosis (Black et al, 2019). Renal fibrosis characterised by progressive tissue scarring is a hallmark of CKD and a prominent feature of AAN.…”

Section: Discussionmentioning

confidence: 99%

“…Nonetheless, this study allowed us to identify validated pathways that were specifically regulated by MSC-EVs which include: apoptosis, TGFβ, FAS, and P53 signalling pathways amongst others that have been reported to play a role in CKD (Chung and Lan, 2015;Kholia et al, 2018;Black et al, 2019;Grange et al, 2019b). Moreover, the comparison between miRNAs regulated by MSC-EVs in the current study and HLSC-EVs in our previous study (Kholia et al, 2018), showed no overlap, suggesting that the molecular targets of stem cell derived EVs could differ despite their overall common therapeutic effect.…”

Section: Discussionmentioning

confidence: 99%

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Mesenchymal Stem Cell Derived Extracellular Vesicles Ameliorate Kidney Injury in Aristolochic Acid Nephropathy

Kholia

Sanchez

Cedrino

et al. 2020

Front. Cell Dev. Biol.

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Limitations in the current therapeutic strategies for the prevention of progression of chronic kidney disease (CKD) to end stage renal disease has been a drawback to improving patient recovery. It is therefore imperative that a solution is found to alleviate this problem and improve the health and well-being of patients overall. Aristolochic acid (AA) induced nephropathy, a type of nephrotoxic CKD is characterised by cortical tubular injury, inflammation, leading to interstitial fibrosis. Extracellular vesicles derived from human bone marrow mesenchymal stem cells (MSC-EVs) display therapeutic properties in various disease models including kidney injury. In the current study, we intended to investigate the ability of MSC-EVs on ameliorating tubular injury and interstitial fibrosis in a mouse model of aristolochic acid nephropathy (AAN). The chronic model of AAN is comprised of an intraperitoneal injection of AA in NSG mice, followed by a three-day incubation period and then inoculation of MSC-EVs intravenously. This routine was performed on a weekly basis for four consecutive weeks, accompanied by the monitoring of body weight of all mice. Blood and tissue samples were collected post sacrifice. All animals administered with AA developed kidney injury and renal fibrosis. A gradual loss of body weight was observed, together with a deterioration in kidney function. Although no significant recovery was observed in weight loss following treatment with MSC-EVs, a significant reduction in: blood creatinine and blood urea nitrogen (BUN), tubular necrosis, and interstitial fibrosis was observed. In addition, infiltration of CD45 positive immune cells, fibroblasts, and pericytes which were elevated in the interstitium post AA induced injury, were also significantly reduced by MSC-EVs. Kidneys were also subjected to molecular analyses to evaluate the regulation of profibrotic genes. MSC-EVs significantly reduced AA induction of the pro-fibrotic genes α-Sma, Tgfb1 and Col1a1. A downregulation in pro-fibrotic genes was also observed in fibroblasts activated by AA injured mTECs in vitro. Furthermore, meta-analyses of miRNAs downregulated by MSC-EVs, such as miR21, revealed the regulation of multiple

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Mesenchymal Stem Cell Derived Extracellular Vesicles Ameliorate Kidney Injury in Aristolochic Acid Nephropathy

Kholia

Sanchez

Cedrino

et al. 2020

Front. Cell Dev. Biol.

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“…The production of proinflammatory cytokines/chemokines is a key initiating step in renal fibrogenesis. 26 Therefore, we examined the expression of some proinflammatory cytokines/chemokines, including MCP-1, RANTES, TNF-α, and IL-1β, in the kidney by enzyme-linked immunosorbent assay (ELISA). The results showed that the levels of these molecules were significantly increased in the kidney of HN rats.…”

Section: Ppar-γ Activation Inhibits the Release Of Cytokines/chemokinmentioning

confidence: 99%

<p>Treatment with a PPAR-γ Agonist Protects Against Hyperuricemic Nephropathy in a Rat Model</p>

Wang¹,

Deng²,

Xiong³

et al. 2020

DDDT

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Hyperuricemia is an independent risk factor for renal damage and can promote the progression of chronic kidney disease (CKD). In the present study, we employ a rat model to investigate the effects of rosiglitazone (RGTZ), a peroxisome proliferator-activated receptorgamma agonist, on the development of hyperuricemic nephropathy (HN), and we elucidate the mechanisms involved. Methods: An HN rat model was established by oral administration of a mixture of adenine and potassium oxonate daily for 3 weeks. Twenty-four rats were divided into 4 groups: sham treatment, sham treatment plus RGTZ, HN, and HN treated with RGTZ. Results: Administration of RGTZ effectively preserved renal function, decreased urine microalbumin, and inhibited interstitial fibrosis and macrophage infiltration in a rat HN model. RGTZ treatment also inhibited TGF-β and NF-κB pathway activation, decreased expression of fibronectin, collagen I, α-SMA, vimentin, MCP-1, RANTES, TNF-α, and IL-1β, and increased E-cadherin expression in the kidneys of HN rats. Furthermore, RGTZ treatment preserved expression of OAT1 and OAT3 in the kidney of HN rats. Conclusion: RGTZ attenuates the progression of HN through inhibiting TGF-β signaling, suppressing epithelial-to-mesenchymal transition, reducing inflammation, and lowering serum uric acid levels by preserving expression of urate transporters.

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“… 23 Chronic fibrotic conditions in dermal, lung, liver, and kidney tissue are also characterized by myofibroblast persistence. 24 , 25 , 26 , 27 Thus, targeting myofibroblasts is a goal of fibrotic therapies, and the transparent cornea is an interesting and accessible model system for testing even non-ocular anti-fibrotic therapies. 20 …”

Section: Introductionmentioning

confidence: 99%

USP10 Targeted Self-Deliverable siRNA to Prevent Scarring in the Cornea

Boumil

Castro

Phillips

et al. 2020

Molecular Therapy - Nucleic Acids

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Ocular scarring after surgery, trauma, or infection leads to vision loss. The transparent cornea is an excellent model system to test anti-scarring therapies. Cholesterol-conjugated fully modified asymmetric small interfering RNAs (siRNAs) (selfdeliverable siRNAs [sdRNAs]) are a novel modality for in vivo gene knockdown, transfecting cells and tissues without any additional formulations. Myofibroblasts are a main contributor to scarring and fibrosis. a v integrins play a central role in myofibroblast pathological adhesion, overcontraction, and transforming growth factor b (TGF-b) activation. Previously, we demonstrated that a v integrins are protected from intracellular degradation after wounding by upregulation of the deubiquitinase (DUB) ubiquitin-specific protease 10 (USP10), leading to integrin cell surface accumulation. In this study, we tested whether knockdown of USP10 with a USP10-targeting sdRNA (termed US09) will reduce scarring after wounding a rabbit cornea in vivo. The wounded corneal stroma was treated once with US09 or non-targeting control (NTC) sdRNA. At 6 weeks US09 treatment resulted in faster wound closure, limited scarring, and suppression of fibrotic markers and immune response. Specifically, fibronectin-extra domain A (EDA), collagen III, and a-smooth muscle actin (p < 0.05), CD45 + cell infiltration (p < 0.01), and apoptosis at 24 (p < 0.01) and 48 h (p < 0.05) were reduced post-wounding. Corneal thickness and cell proliferation were restored to unwounded parameters. Targeting the DUB, USP10 is a novel strategy to reduce scarring. This study indicates that ubiquitin-mediated pathways should be considered in the pathogenesis of fibrotic healing.

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Renal Inflammation and Fibrosis: A Double-edged Sword

Cited by 100 publications

References 202 publications

Mesenchymal Stem Cell Derived Extracellular Vesicles Ameliorate Kidney Injury in Aristolochic Acid Nephropathy

Mesenchymal Stem Cell Derived Extracellular Vesicles Ameliorate Kidney Injury in Aristolochic Acid Nephropathy

<p>Treatment with a PPAR-γ Agonist Protects Against Hyperuricemic Nephropathy in a Rat Model</p>

USP10 Targeted Self-Deliverable siRNA to Prevent Scarring in the Cornea

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