Kidney Week

Abstract: SA-PO1159

Mitofusins by Regulating Lung Macrophage-Derived Immune Signals Modulate Monocyte Migration and Interorgan Cross-Talk during Kidney Fibrosis

Session Information

• CKD: Mechanisms - 3
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Bhatia, Divya, Weill Cornell Medicine, New York, New York, United States

Divya Bhatia, PhD

• Patiño, Edwin, Weill Cornell Medicine, New York, New York, United States

Edwin Patiño, MD

• Kallinos, Eleni, Weill Cornell Medicine, New York, New York, United States

Eleni Kallinos

• Plataki, Maria, Weill Cornell Medicine, New York, New York, United States

Maria Plataki, MD, PhD

• Choi, Augustine MK, Weill Cornell Medicine, New York, New York, United States

Augustine MK Choi, MD

• Choi, Mary E., Weill Cornell Medicine, New York, New York, United States

Mary E. Choi, MD

Background

Chronic kidney disease (CKD)-associated lung injury is under-recognized. Coexistence of lung dysfunction with CKD increases rates of kidney failure and mortality. We studied alveolar macrophage (AM) and type 2 alveolar epithelial cell (AEC2)-specific roles of mitochondrial fusion proteins, mitofusin (MFN)1 and MFN2 in kidney fibrosis-associated lung injury and interorgan crosstalk.

Methods

Myeloid-(LysM-Cre^+/-) or AEC2 (Spc-Cre^+/-)-specific Mfn1^+/- and/or Mfn2^+/- & control mice were subjected to unilateral ureteral obstruction (UUO) or sham surgery (7-days), or adenine or control diet (4 or 8-weeks). Lungs, kidneys, & bronchoalveolar lavage fluid (BALF) were analyzed by western blot, Masson’s trichrome staining, & flow cytometry. Blood was assessed for blood urea nitrogen (BUN), creatinine, chemokine analysis (bead array) & flow cytometry. THP-1 cells were treated with TGF-β1 and/or PGC-1α agonist.

Results

CKD-associated monocyte infiltration in the lungs, AM-derived inflammatory (mitochondrial-specific reactive oxygen species (mROS), Ly6C^high) & fibrotic (CX3CR1, galectin-3, arginase-I) signals were suppressed in myeloid-specific Mfn1^+/- and/or Mfn2^+/- mice. Protection in myeloid-specific Mfn1^+/- and/or Mfn2^+/- mice was mediated by AEC2-specific compensatory inductions of MFN1/MFN2 during CKD. AEC2-specific Mfn1^+/- and/or Mfn2^+/- mice after UUO had increased monocytes in the lungs and BALF. After UUO, interstitial, monocyte-derived, and tissue-resident alveolar macrophages from lungs and BALF of AEC2-specific Mfn1^+/- and/or Mfn2^+/- mice displayed increased mROS & galectin-3. AEC2-specific Mfn1^+/- and/or Mfn2^+/- mice after UUO had increased levels of i) BUN & creatinine, ii) circulating CCL-17, 22, TGF-β1, IL-12p40, & iii) CCR2+, Ly6C^high, mROS+ monocytes. TGF-β1 promoted, while PGC-1α agonist suppressed migratory, inflammatory, and profibrotic functions of THP-1 monocytes.

Conclusion

Myeloid lineage-specific Mfn1/Mfn2 ablation attenuated CKD-associated lung injury via a compensatory induction of MFN1/MFN2 in AEC2. AEC2-specific loss of Mfn1/Mfn2 accelerated kidney fibrosis-associated lung macrophage-derived local and circulating inflammatory signals. Circulating immune signals by promoting monocytes' infiltration into the kidney, can exaggerate kidney inflammation and fibrosis.

Funding

• Other NIH Support