The macrocyclic lactone Oxacyclododecindione reduces fibrosis progression
#### Authors
Sabrina Saurin, Myriam Meineck, Markus Rohr, Wilfried Roth, Till Opatz, Gerhard Erkel, Andrea Pautz, Julia Weinmann-Menke
#### Background
Renal fibrosis is one of the most important triggers of chronic kidney disease and only a very limited number of therapeutic options are available to stop fibrosis progression. As fibrosis is characterized by inflammation, myofibroblast activation and extracellular matrix deposition, a drug that is able to address all these processes might be an interesting therapeutic option.
#### Methods
We tested _in vivo_ in an ischemia reperfusion (I/R) model in C57BL/6 mice and in kidney tubular epithelial cells (HK2 cell line and primary cells) and whether the natural product oxacyclododecindione (Oxa) reduces fibrosis progression in kidney disease. This was evaluated by western blot, mRNA expression, and mass spectrometry secretome analyses as well as by immunohistochemistry.
#### Results
Indeed, Oxa blocked expression of epithelial-mesenchymal transition marker proteins, reduced renal damage, immune cell infiltration and collagen expression and deposition, both _in vivo_ and _in vitro_. Remarkebly, the beneficial effects of Oxa were detected also when the natural product was administered at a time point of established fibrotic changes, a situation that is close to the clinical situation. Initial _in vitro_ experiments demonstrated, that a synthetic Oxa derivative possess similar features.
#### Conclusion
Although open questions such as possible side effects need to be investigated, we believe that the combination of anti-inflammatory and anti-fibrotic effects of Oxa make the substance a promising candidate for a new therapeutif approach in fibrosis treatment and therefore the prevention of progression of keidney disease.
### Sample processing protocol
HK2 cells were stimulated and supernatant prepared as described in the publication. Mass spectrometry analysis was performed on a high-resolution LC-MS system (Eksigent nanoLC 425 coupled to a Triple-TOF 6600, AB Sciex) in information dependent acquisition (IDA) mode. For detailed information, see supplemental methods.
