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Abstract: FR-PO1069

Alveolar Type II Cell-Specific Mitofusins Modulate Kidney Fibrosis and Associated Lung Injury

Session Information

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms

Authors

  • Bhatia, Divya, Weill Cornell Medicine, New York, New York, United States
  • Kallinos, Eleni, Weill Cornell Medicine, New York, New York, United States
  • Patino, Edwin, Weill Cornell Medicine, New York, New York, United States
  • Plataki, Maria, Weill Cornell Medicine, New York, New York, United States
  • Choi, Augustine MK, Weill Cornell Medicine, New York, New York, United States
  • Choi, Mary E., Weill Cornell Medicine, New York, New York, United States
Background

Chronic kidney disease (CKD)-associated lung injury and implications of deleterious lung-kidney crosstalk on the progression of kidney fibrosis are under-recognized. Mitochondrial fusion proteins, mitofusin (MFN)1 and MFN2, play critical roles in regulating mitochondrial physiological function, which is essential for kidney homeostasis. We studied the effects of type II alveolar epithelial cell (AEC II)-specific loss of Mfn1 or Mfn2 on kidney fibrosis and associated lung injury during CKD.

Methods

AEC II (Spc-Cre+/-)-specific Mfn1 (Mfn1fl/fl) or Mfn2 (Mfn2fl/fl-) knockout (KO) and control (Spc-Cre+/-) mice were subjected to unilateral ureteral obstruction (UUO) or sham surgery (7-days) or fed with adenine (AD) or control diet (28-days). Kidneys, lungs, blood, and bronchoalveolar lavage (BAL) fluid were analyzed by western blot, Masson’s trichrome staining, and flow cytometry. Serum creatinine (Scr) and blood urea nitrogen (BUN) were measured.

Results

MFN1 and MFN2 in AEC II (EpCAM+ CD45-), lungs, and kidneys decreased while pro-inflammatory monocytes (CCR2+ Ly6C+ CD11b+) in blood, kidneys, lungs, and BAL fluid increased after UUO or AD. AEC II-specific Mfn1 or Mfn2 KO mice displayed higher expression of fibronectin, arginase-I, galectin-3, IL-1β, and TGF-β1, and collagen deposition in the kidneys and lungs after UUO than control mice. Mfn1 or Mfn2 loss in AEC II resulted in increased kidney macrophages (KM, CD11b+ F4/80+ CD45+) in obstructed kidneys and increased alveolar macrophages (AM, siglecf F+ CD11C+ CD45+) in the lungs and BAL fluid after UUO. KM and AM from AEC II-specific Mfn1 or Mfn2 KO mice exhibited higher mitochondrial-specific reactive oxygen species and galectin-3 after UUO than control mice. Moreover, AEC II-specific Mfn2 KO mice displayed a lower number of proximal tubular cells (megalin+ CD45-) in obstructed kidneys, and higher BUN and Scr levels than control mice after UUO.

Conclusion

In 2 models of kidney fibrosis, we show downregulation of MFN1/2 in both the lungs and kidneys. AEC II-specific loss of Mfn(s) augmented inflammatory and fibrotic responses in KM and AM during CKD, suggesting the role of macrophages in inter-organ crosstalk. Mitochondrial-derived damage-associated molecular patterns from AM and injured AEC II may be involved in deleterious lung-kidney crosstalk and aggravate kidney fibrosis.

Funding

  • Other NIH Support