Browsing by Author "Pons, Marianne"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    GDF11 induces kidney fibrosis, renal cell epithelial-to-mesenchymal transition, and kidney dysfunction and failure
    (Elsevier, 2018-08) Pons, Marianne; Koniaris, Leonidas G.; Moe, Sharon M.; Gutierrez, Juan C.; Esquela-Kerscher, Aurora; Zimmers, Teresa A.; Surgery, School of Medicine
    BACKGROUND: GDF11 modulates embryonic patterning and kidney organogenesis. Herein, we sought to define GDF11 function in the adult kidney and in renal diseases. METHODS: In vitro renal cell lines, genetic, and murine in vivo renal injury models were examined. RESULTS: Among tissues tested, Gdf11 was highest in normal adult mouse kidney. Expression was increased acutely after 5/6 nephrectomy, ischemia-reperfusion injury, kanamycin toxicity, or unilateral ureteric obstruction. Systemic, high-dose GDF11 administration in adult mice led to renal failure, with accompanying kidney atrophy, interstitial fibrosis, epithelial-to-mesenchymal transition of renal tubular cells, and eventually death. These effects were associated with phosphorylation of SMAD2 and could be blocked by follistatin. In contrast, Gdf11 heterozygous mice showed reduced renal Gdf11 expression, renal fibrosis, and expression of fibrosis-associated genes both at baseline and after unilateral ureteric obstruction compared with wild-type littermates. The kidney-specific consequences of GDF11 dose modulation are direct effects on kidney cells. GDF11 induced proliferation and activation of NRK49f renal fibroblasts and also promoted epithelial-to-mesenchymal transition of IMCD-3 tubular epithelial cells in a SMAD3-dependent manner. CONCLUSION: Taken together, these data suggest that GDF11 and its downstream signals are critical in vivo mediators of renal injury. These effects are through direct actions of GDF11 on renal tubular cells and fibroblasts. Thus, regulation of GDF11 presents a therapeutic target for diseases involving renal fibrosis and impaired tubular function.
  • Thumbnail Image
    Item
    SOCS3 is a novel bi-functional regulator of muscle growth and wasting
    (Office of the Vice Chancellor for Research, 2015-04-17) Bonetto, Andrea; Camperi, Andrea; Aydogdu, Tufan; Pons, Marianne; Au, Ernie D.; Koniaris, Leonidas G.; Zimmers, Teresa A.
    Disease states such as cancer and other inflammatory conditions often show elevated IL-6 levels that correlate with muscle wasting and mortality. Previously we reported that STAT3, a transcription factor downstream of IL-6 binding to its receptor, plays a causative role in cancer cachexia, and that STAT3 inhibition prevents muscle wasting. Others have also shown that STAT3 blockade rescues cachexia in a murine model of kidney failure. Altogether these results established STAT3 as a regulator of muscle mass. One of STAT3 downstream target genes is the Suppressor of cytokine signaling-3 (SOCS-3). Interestingly, SOCS3 has been reported to inhibit the IL-6/STAT3 signaling by means of a feedback mechanism. In particular, SOCS3 can prevent further STAT3 activation by inhibiting the activation of JAK kinases, competing for receptor binding motifs and targeting the receptor for proteasomal degradation. We thus sought to determine the role of SOCS3 in muscle growth regulation and whether SOCS3 can improve muscle wasting in conditions of high IL-6. Adenoviral-mediated SOCS3 overexpression in C2C12 myotubes caused hypertrophy and rescued IL-6-induced myofiber shrinkage. Similarly, SOCS3 gene transfer in the tibialis muscle of tumor hosts and burn-injured mice prevented muscle atrophy due to elevated IL-6. We then generated MLC-SOCS3 transgenic mice overexpressing SOCS3 from a muscle-specific promoter. Interestingly, these animals exhibit a complex sexually dimorphic phenotype. Indeed, female mice showed higher SOCS3 protein levels in skeletal muscle compared to the males, consistently with decreased pSTAT3 expression. Despite reduced or unchanged body weights, the MLC-SOCS3 transgenics generally showed larger skeletal muscles compared to their wild-type littermates. 1-weekold and adult MLC-SOCS3 mice were also characterized by significantly larger muscle cross-sectional area. However, only adult male mice showed reduced number of muscle fibers and increased number of central nuclei, thus suggesting that SOCS3 could affect myogenesis and differentiation. On this line and consistent with previous reports, primary myoblasts isolated from MLC-SOCS3 mice were shown to proliferate at a lower rate and formed hypertrophic fibers upon differentiation. Furthermore, MLC-SOCS3 myotubes as well as C2C12 expressing SOCS3 were refractory to both catabolic (IL-6) and anabolic (IGF-1 and GH) stimuli. These data suggest that SOCS3 could act as a bi-functional regulator of muscle growth, possibly by affecting differentiation and limiting both IL-6/STAT3- induced wasting as well as IGF-1/GH-associated signaling. Further investigation is needed to define whether SOCS3 may play a role in the activation of muscle satellite cells and to support the use of SOCS3 as a therapeutic approach in cachexia and sarcopenia.
  • Thumbnail Image
    Item
    The systemic activin response to pancreatic cancer: implications for effective cancer cachexia therapy
    (Wiley, 2019-10) Zhong, Xiaoling; Pons, Marianne; Poirier, Christophe; Jiang, Yanlin; Liu, Jianguo; Sandusky, George E.; Shahda, Safi; Nakeeb, Attila; Schmidt, C. Max; House, Michael G.; Ceppa, Eugene P.; Zyromski, Nicholas J.; Liu, Yunlong; Jiang, Guanglong; Couch, Marion E.; Koniaris, Leonidas G.; Zimmers, Teresa A.; Surgery, School of Medicine
    BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy partly due to frequent, severe cachexia. Serum activin correlates with cachexia and mortality, while exogenous activin causes cachexia in mice. METHODS: Isoform-specific activin expression and activities were queried in human and murine tumours and PDAC models. Activin inhibition was by administration of soluble activin type IIB receptor (ACVR2B/Fc) and by use of skeletal muscle specific dominant negative ACVR2B expressing transgenic mice. Feed-forward activin expression and muscle wasting activity were tested in vivo and in vitro on myotubes. RESULTS: Murine PDAC tumour-derived cell lines expressed activin-βA but not activin-βB. Cachexia severity increased with activin expression. Orthotopic PDAC tumours expressed activins, induced activin expression by distant organs, and produced elevated serum activins. Soluble factors from PDAC elicited activin because conditioned medium from PDAC cells induced activin expression, activation of p38 MAP kinase, and atrophy of myotubes. The activin trap ACVR2B/Fc reduced tumour growth, prevented weight loss and muscle wasting, and prolonged survival in mice with orthotopic tumours made from activin-low cell lines. ACVR2B/Fc also reduced cachexia in mice with activin-high tumours. Activin inhibition did not affect activin expression in organs. Hypermuscular mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not mortality when implanted with orthotopic tumours. Human tumours displayed staining for activin, and expression of the gene encoding activin-βA (INHBA) correlated with mortality in patients with PDAC, while INHBB and other related factors did not. CONCLUSIONS: Pancreatic adenocarcinoma tumours are a source of activin and elicit a systemic activin response in hosts. Human tumours express activins and related factors, while mortality correlates with tumour activin A expression. PDAC tumours also choreograph a systemic activin response that induces organ-specific and gene-specific expression of activin isoforms and muscle wasting. Systemic blockade of activin signalling could preserve muscle and prolong survival, while skeletal muscle-specific activin blockade was only protective for weight loss. Our findings suggest the potential and need for gene-specific and organ-specific interventions. Finally, development of more effective cancer cachexia therapy might require identifying agents that effectively and/or selectively inhibit autocrine vs. paracrine activin signalling.