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Kidney Week

Abstract: PO0651

A Novel Small Molecule Modulating the Mitochondrial NEET Proteins Improves Inflammation and Fibrosis in Kidneys of Nonalcoholic Steatohepatitis Mice

Session Information

  • CKD Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Terzi, Fabiola, Institut Necker-Enfants Malades, Paris, Île-de-France, France
  • Le Corre, Stéphanie, ENYO Pharma SA, Lyon, Auvergne-Rhône-Alpes , France
  • Vasseur, Florence, Institut Necker-Enfants Malades, Paris, Île-de-France, France
  • Sampson, Diane, ENYO Pharma SA, Lyon, Auvergne-Rhône-Alpes , France
  • Radreau, Pauline, ENYO Pharma SA, Lyon, Auvergne-Rhône-Alpes , France
  • De Chassey, Benoit, ENYO Pharma SA, Lyon, Auvergne-Rhône-Alpes , France
  • Vonderscher, Jacky, ENYO Pharma SA, Lyon, Auvergne-Rhône-Alpes , France
  • Darteil, Raphael, ENYO Pharma SA, Lyon, Auvergne-Rhône-Alpes , France
  • Meldrum, Eric, ENYO Pharma SA, Lyon, Auvergne-Rhône-Alpes , France
Background

Non-alcoholic steatohepatitis (NASH) is a disease characterized by excessive fat accumulation, inflammation, and ballooning degeneration of hepatocytes, with or without fibrosis in the liver. It is now reported that NASH not only affects the liver but is also associated with chronic kidney disease (CKD). However, the morphological appearance of NASH kidneys has been poorly characterized. These observations highlight the need for a treatment that targets both conditions. Here, we assessed the effect of a novel chemistry that regulates the function of 3 mitochondrial proteins called the NEET proteins, previously reported to be important in metabolic diseases, on a diet-induced NASH model in mice.

Methods

Mice were fed with a high fat diet for 30 weeks prior treatment with ENYO’s molecule for 8 weeks. The kidneys and livers were collected at sacrifice and sections were stained with H&E, PAS and picrosirius red staining to analyze their morphology. Specific immunostainings and qRT-PCR were performed to quantify the extent of inflammation (CD3, MAC1 and F4/80) and fibrosis (Col1a1, Col3a1, fibronectin).

Results

NASH mice displayed severe renal lesions such as glomerulosclerosis, tubular casts, tubular lipid accumulation and interstitial fibrosis. Mononuclear cell infiltration was also massively increased, in particular in the perivascular areas. Quantitative RT-PCR revealed a significant increase of the expression of several fibrosis and inflammation markers. Therapeutic administration of ENYO’s molecule was shown to resolve these lesions with a return back to normal regarding fibrosis, and a 50% and 35% decrease in lymphocyte and macrophage accumulation, respectively. In the liver, inflammation and fibrosis were also attenuated, specifically in the periportal zone that has been shown to be correlated with the severity of the disease. Interestingly, the most significant responders in the liver were also the best responders in the kidneys.

Conclusion

We have shown that NASH mice developed CKD, recapitulating the phenotypes observed in humans. Moreover, we have identified a new treatment, that by targeting NEET proteins, protects mice from the development of both liver and renal lesions.