Kidney Week

Abstract: SA-PO837

Mitochondrial Dysfunction in FOXD1 Lineage Cells Is Associated with Renal Fibrogenesis and Anemia

Session Information

• Molecular Mechanisms of CKD - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 1903 CKD (Non-Dialysis): Mechanisms

Authors

• Kobayashi, Hanako, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Hanako Kobayashi,

• Ishii, Ken, Vanderbilt University Medical Center, Nashville, Tennessee, United States

Ken Ishii,

• Haase, Volker H., Vanderbilt University Medical Center, Nashville, Tennessee, United States

Volker H. Haase,

Background

Mitochondria play an important role in the pathophysiology of chronic kidney diseases (CKD), as mitochondrial uncoupling and dysfunction changes cellular metabolism impacting CKD pathogenesis and its progression. It is well established that renal function impairment correlates with the degree of tubulointerstitial fibrosis. Furthermore, fate-mapping studies have previously shown that the majority of collagen-producing renal myofibroblasts are derived from perivascular interstitial cells and pericytes. Despite the importance of these findings for renal fibrogenesis, the role of mitochondria and oxidative phosphorylation in renal interstitial cell function and myofibroblast transdifferentiation is only poorly understood.

Methods

To investigate mitochondrial function and the role of oxidative phosphorylation in renal interstitial cells, we have generated and analyzed mice with interstitial cell-specific inactivation of mitochondrial transcription factor A (TFAM) using FoxD1-cre transgenics. TFAM is required for mitochondrial gene transcription and DNA replication and thus essential for the maintenance of mitochondrial function and mass.

Results

We demonstrate that suppression of mitochondrial function in interstitial cells has a pivotal role in the pathogenesis of CKD, as inactivation of stromal TFAM resulted in progressive renal failure (BUN at 6-weeks of age: 76.0 ± 1.5 mg/dl vs. 27.8 ± 0.9 mg/dl in control; p<0.0001, n=4 each), which was associated with an increased number of α-SMA-expressing cells, the development of tubulointerstitial fibrosis and proteinuria at older age. Furthermore, interstitial cell-specific TFAM knockout mice developed anemia (Hct: 42.8 ± 1.5 % in control vs. 36.2 ± 1.0 % in mutants; p= 0.006, n=5 each) and were characterized by a reduction in their capacity to produce erythropoietin in response to hypoxic stimuli, a major pathologic feature of CKD.

Conclusion

Our data demonstrate that mitochondria play an important role in the maintenance of normal renal interstitial cell homeostasis and hypoxia responses. A detailed metabolic characterization of interstitial cell-specific TFAM knockout mice will be presented at the meeting. <!-- Copyright (c) 2006 Microsoft Corporation. All rights reserved. --><!-- OwaPage = ASP.webreadyviewbody_aspx --><!--Copyright (c) 2006 Microsoft Corporation. All rights reserved.-->

Funding

• NIDDK Support