ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

ASN / Education & Meetings / Kidney Week /

Please note that you are viewing an archived section from 2021 and some content may be unavailable. To unlock all content for 2021, please visit the archives.

Abstract: PO0729

The Essential Role of Intact Mitochondrial Substrate Balance in Preventing Renal Injury

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Mccrimmon, Allison N., Pennington Biomedical Research Center, Baton Rouge, Louisiana, United States
  • Cahill, Kerin M., Pennington Biomedical Research Center, Baton Rouge, Louisiana, United States
  • Ilatovskaya, Daria, Medical University of South Carolina, Charleston, South Carolina, United States
  • Stadler, Krisztian, Pennington Biomedical Research Center, Baton Rouge, Louisiana, United States
Background

Alterations in mitochondrial function are linked to the development of chronic/diabetic kidney diseases. Proximal tubular cells (PTCs) are highly energy demanding, covering this need mostly from mitochondrial fatty acid oxidation. It is suggested, but not entirely clear whether derailments in mitochondrial metabolism and function are forerunners of tubular damage. In our previous studies we modeled mitochondrial substrate overload - an important aspect of metabolic disease - by creating mice lacking the enzyme carnitine acetyl-transferase (CrAT) in the PTC. These studies revealed that mitochondrial substrate overload in proximal tubules causes tubular injury and secondary glomerulosclerosis.

Methods

Here we demonstrate the importance of intact mitochondrial substrate efflux by titrating the amount of overload through the generation of a heterozygous CrAT knockout mouse model (“PT-CrATHET” mouse). We used an integrated approach of imaging, electron microscopy, functional studies (mitochondrial/cell respiration) and Next Generation RNA Sequencing combined with Ingenuity Pathway Analysis.

Results

PT-CrATHET mice developed tubular and glomerular injury similarly to their homozygous counterparts (N=5-7 mice examined, at least three separate cohorts). Mitochondria were structurally and functionally impaired in both sexes. Transcriptomic analyses, however, revealed striking differences in the pathways leading to renal injury in males vs females (evaluated using NextGenSeq and IPA with a threshold of P<0.1). In response to CrAT haploinsufficiency, males almost completely shut down fatty acid oxidation and related pathways. Females had a much weaker transcriptional response in metabolism-related pathways but activation of inflammation was more prominent when compared to males. Proximal tubular cells from these animals exhibited a shift in metabolism towards a more glycolytic phenotype (N=8 biological replicates, P<0.05 in at least three independent experiments), which was also more pronounced in males.

Conclusion

Our findings demonstrate that maintaining an intact mitochondrial substrate metabolism balance is crucial for the PTC. Potentially broad implications are: the metabolic shift and the sexual dimorphisms discovered herein offer new intervention points for the future and novel approaches to consider for treating kidney disease.

Funding

  • NIDDK Support