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

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), Ly6Chigh) & 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+, Ly6Chigh, 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 - NHLBI (2T32HL134629-06A1)