Transglutaminase inhibition ameliorates experimental diabetic nephropathy

Diabetic nephropathy is characterized by excessive extracellular matrix accumulation resulting in renal scarring and end-stage renal disease. Previous studies have suggested that transglutaminase type 2, by formation of its protein crosslink product epsilon-(gamma-glutamyl)lysine, alters extracellular matrix homeostasis, causing basement membrane thickening and expansion of the mesangium and interstitium. To determine whether transglutaminase inhibition can slow the progression of chronic experimental diabetic nephropathy over an extended treatment period, the inhibitor NTU281 was given to uninephrectomized streptozotocin-induced diabetic rats for up to 8 months. Effective transglutaminase inhibition significantly reversed the increased serum creatinine and albuminuria in the diabetic rats. These improvements were accompanied by a fivefold decrease in glomerulosclerosis and a sixfold reduction in tubulointerstitial scarring. This was associated with reductions in collagen IV accumulation by 4 months, along with reductions in collagens I and III by 8 months. This inhibition also decreased the number of myofibroblasts, suggesting that tissue transglutaminase may play a role in myofibroblast transformation. Our study suggests that transglutaminase inhibition ameliorates the progression of experimental diabetic nephropathy and can be considered for clinical application.

Synthesis of potent water-soluble tissue transglutaminase inhibitors

Dipeptide-based sulfonium peptidylmethylketones derived from 6-diazo-5-oxo-L-norleucine (DON) have been investigated as potential water-soluble inhibitors of extracellular transglutaminase. The lead compounds were prepared in four steps and exhibited potent activity against tissue transglutaminase.

Inhibition of transglutaminase activity reduces extracellular matrix accumulation induced by high glucose levels in proximal tubular epithelial cells

Diabetic nephropathy affects 30-40% of diabetics leading to end-stage kidney failure through progressive scarring and fibrosis. Previous evidence suggests that tissue transglutaminase (tTg) and its protein cross-link product epsilon(gamma-glutamyl)lysine contribute to the expanding renal tubulointerstitial and glomerular basement membranes in this disease. Using an in vitro cell culture model of renal proximal tubular epithelial cells we determined the link between elevated glucose levels with changes in expression and activity of tTg and then, by using a highly specific site directed inhibitor of tTg (1,3-dimethyl-2[(oxopropyl)thio]imidazolium), determined the contribution of tTg to glucose-induced matrix accumulation. Exposure of cells to 36 mm glucose over 96 h caused an mRNA-dependent increase in tTg activity with a 25% increase in extracellular matrix (ECM)-associated tTg and a 150% increase in ECM epsilon(gamma-glutamyl)lysine cross-linking. This was paralleled by an elevation in total deposited ECM resulting from higher levels of deposited collagen and fibronectin. These were associated with raised mRNA for collagens III, IV, and fibronectin. The specific site-directed inhibitor of tTg normalized both tTg activity and ECM-associated epsilon(gamma-glutamyl)lysine. Levels of ECM per cell returned to near control levels with non-transcriptional reductions in deposited collagen and fibronectin. No changes in transforming growth factor beta1 (expression or biological activity) occurred that could account for our observations, whereas incubation of tTg with collagen III indicated that cross-linking could directly increase the rate of collagen fibril/gel formation. We conclude that Tg inhibition reduces glucose-induced deposition of ECM proteins independently of changes in ECM and transforming growth factor beta1 synthesis thus opening up its possible application in the treatment other fibrotic and scarring diseases where tTg has been implicated.

Transglutaminase inhibition reduces fibrosis and preserves function in experimental chronic kidney disease

Progressive tissue fibrosis is involved in debilitating diseases that affect organs including the lungs, liver, heart, skin, and kidneys. Recent evidence suggests that tissue transglutaminase, an enzyme that crosslinks proteins, may be involved in tissue fibrosis by crosslinking and stabilizing the extracellular matrix or by recruiting and activating the large latent transforming growth factor (TGF)-β1 complex. We treated rats that had undergone 5/6-nephrectomy with two different irreversible inhibitors of transglutaminase and found that both prevented a decline in kidney function and reduced the development of glomerulosclerosis and tubulointerstitial fibrosis by up to 77% and 92%, respectively. Treatment reduced the accumulation of collagen I and collagen III, with the primary mechanism of action being direct interference with the crosslinking of extracellular matrix rather than altered regulation of TGFβ1. We conclude that inhibition of transglutaminase offers a potential therapeutic option for chronic kidney disease and other conditions that result from tissue fibrosis. Copyright © 2007 by the American Society of Nephrology.

IL-1α and inflammasome-independent IL-1β promote neutrophil infiltration following alum vaccination

Despite its long record of successful use in human vaccines, the mechanisms underlying the immunomodulatory effects of alum are not fully understood. Alum is a potent inducer of interleukin-1 (IL-1) secretion in vitro in dendritic cells and macrophages via Nucleotide-binding domain and leucine-rich repeat-containing (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome activation. However, the contribution of IL-1 to alum-induced innate and adaptive immune responses is controversial and the role of IL-1α following alum injection has not been addressed. This study shows that IL-1 is dispensable for alum-induced antibody and CD8 T cell responses to ovalbumin. However, IL-1 is essential for neutrophil infiltration into the injection site, while recruitment of inflammatory monocytes and eosinophils is IL-1 independent. Both IL-1α and IL-1β are released at the site of injection and contribute to the neutrophil response. Surprisingly, these effects are NLRP3-inflammasome independent as is the infiltration of other cell populations. However, while NLRP3 and caspase 1 were dispensable, alum-induced IL-1β at the injection site was dependent on the cysteine protease cathepsin S. Overall, these data demonstrate a previously unreported role for cathepsin S in IL-1β secretion, show that inflammasome formation is dispensable for alum-induced innate immunity and reveal that IL-1α and IL-1β are both necessary for alum-induced neutrophil influx in vivo.

Negligent Eye

This presentation was both an illustrated lecture and a published paper presented at the IMPACT 9 Conference Printmaking in the Post-Print Age, Hangzhou China 2015. It was an extension of the exhibition catalogue essay for the Bluecoat Gallery Exhibition of the same name. In 2014 I curated an exhibition The Negligent Eye at the Bluecoat Gallery in Liverpool as the result of longstanding interest in scanning and 3D printing and the role of these in changing the field of Print within Fine Art Practice. In the aftermath of curatingshow I have continued to reflect on this material with reference to the writings of Vilém Flusser and Hito Steyerl. The work in the exhibition came from a wide range of artists of all generations most of whom are not explicitly located within Printmaking. Whilst some work did not use any scanning technology at all, a shared fascination with the particular translating device of the systematizing ‘eye’ of a scanning digital video camera, flatbed or medical scanner was expressed by all the work in the show. Through writing this paper I aim to extend my own understanding of questions, which arose from the juxtapositions of work and the production of the accompanying catalogue. The show developed in dialogue with curators Bryan Biggs and Sarah-Jane Parsons of the Bluecoat Gallery who sent a series of questions about scanning to participating artists. In reflecting upon their answers I will extend the discussions begun in the process of this research. A kind of created attention deficit disorder seems to operate on us all today to make and distribute images and information at speed. What value do ways of making which require slow looking or intensive material explorations have in this accelerated system? What model of the world is being constructed by the drive to simulated realities toward ever-greater resolution, so called high definition? How are our perceptions of reality being altered by the world-view presented in the smooth colourful ever morphing simulations that surround us? The limitations of digital technology are often a starting point for artists to reflect on our relationship to real-world fragility. I will be looking at practices where tactility or dimensionality in a form of hard copy engages with these questions using examples from the exhibition. Artists included in the show were: Cory Arcangel, Christiane Baumgartner, Thomas Bewick, Jyll Bradley, Maurice Carlin, Helen Chadwick, Susan Collins, Conroy/Sanderson, Nicky Coutts, Elizabeth Gossling, Beatrice Haines, Juneau Projects, Laura Maloney, Bob Matthews, London Fieldworks (with the participation of Gustav Metzger), Marilène Oliver, Flora Parrott, South Atlantic Souvenirs, Imogen Stidworthy, Jo Stockham, Wolfgang Tillmans, Alessa Tinne, Michael Wegerer, Rachel Whiteread, Jane and Louise Wilson. Scanning, Art, Technology, Copy, Materiality.

Future Print Story

Research trip for 5 academics associated with the RCA to give talks and convene workshops at Tokyo University of the Arts and Kyoto City University of the Arts.

Unlearning

Keynote speaker for a one day symposium in Fine Art and Photography at De Montfort University, Leicester. The symposium looked at research as a rigorous process of investigation leading to new knowledge. It was aimed at visual arts practitioners wanting to account for their practices as forms of research. Two key questions were addressed: 1. How can arts practitioners account for the rigour of the methods they use in practice? 2. To what kinds of knowledge can their practices lead? Coutts' keynote looked at the concept of 'Unlearning' used by Marie Luisa Knott to explore what Hannah Arendt first had to do in order to rethink the atrocities carried out by the Nazis in the 20th Century. To be able to think anew means also to find a means for undoing what has previously been thought. Coutts looked to Arendt amongst other thinkers and artists, and used examples from within her own practice, to reflect on rigour in research and methods for legitimising a range of visual practices.

Printmare Against Nature

Nicky Coutts showed a work in the show "Printmare: Against Nature 1", reproducing a miniature storm scene from a Scottish five pound note and an essay titled "Animal Print Suicide" for the accompanying publication "Printmare Against Nature 2". Curated by Finlay Taylor, ‘Against Nature’ was an exhibition exploring conditions of current understandings of geography (or the geo-graphical), natural histories and landscapes. This exhibition concentrated on work that uses print, and the ways in which subtle innovations in this medium are used to investigate some of the complexities that arise when looking at nature in art. An associated publication has been published by Camberwell Press with essays by David Cross and Nicky Coutts, as well as page images by Bob Matthews, Denis Masi, Finlay Taylor, Kate Scrivener and Dick Jewell. Exhibiting artists included Franz Ackermann, Jasone Miranda Bilbao, Sarah Bodman, Ian Brown, Helen Chadwick, Paul Coldwell, Cornford and Cross, Nicky Coutts, Dunhill & O’Brien, Adam Gillam, Oona Grimes, Judith Goddard, Mark Harris, Katsushika Hokusai, Dan Howard-Birt, Susan Johanknecht, James Keith, Serena Korda, Michael Landy, Jo Love, Mike Marshall, Bob Matthews, Julian Opie, Tim O’Riley, Simon Patterson, David Rayson, Rebecca Salter, Kate Scrivener, Jo Stockham, and Herman de Vries.

Vertigo Rising

Sole-authored publication. Five essays on fear of space, irrational gravities and falling, based on the writings of Flusser, Kafka and the Capek brothers. 'Vertigo Rising' was commissioned as a parallel text to accompany a show of the same name at Five Years, (a London Gallery located in a high rise block).