Kidney Week

Abstract: TH-PO1165

Macrophage-Derived Cytokine Mediation of Kidney-Lung Bidirectionally, Deleterious, Interorgan Cross-Talk in Kidney Fibrosis

Session Information

• CKD: Mechanisms, AKI, and Beyond - 1
  November 06, 2025 | 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, MS, 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

• Muthukumar, Thangamani, Weill Cornell Medicine, New York, New York, United States

Thangamani Muthukumar

• 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

The mechanism underlying kidney-lung interaction during chronic kidney disease (CKD) remains understudied. We investigated mitofusin (MFN)1 and MFN2 roles in modulating lung macrophage-derived immune signals during kidney fibrosis in animal models. In patients with interstitial fibrosis and tubular atrophy (IFTA), we examined the association of circulating and urinary macrophage-derived cytokines with biomarkers of kidney function.

Methods

Myeloid-(LysM-Cre^+/-) or type 2 alveolar epithelial cell (AEC2; Spc-Cre^+/-)-specific Mfn1^+/- and/or Mfn2^+/- and control mice were subjected to unilateral ureteral obstruction (UUO) or sham surgery (7-days), or adenine (AD) or control (Ctl) diet (4 or 8-weeks). Lungs, kidneys, and bronchoalveolar lavage fluid were analyzed. Blood was immunophenotyped and assessed for chemokines, blood urea nitrogen (BUN), and creatinine. Circulating and urinary macrophage-derived cytokines and kidney function panel were analyzed in patients with (n=7) or without (n=9) IFTA by bead array.

Results

AEC2 but not myeloid-specific Mfn1/2 loss promoted kidney fibrosis-associated lung injury, monocytes/macrophages, their galectin-3 expression, and oxidative stress in the lungs. AEC2-specific Mfn1^+/-/Mfn2^+/- ablation increased circulating levels of macrophage-derived cytokines (CCL17, CCL22, TGF-β1, IL-12p40), inflammatory monocytes (Ly6C^high, CD11b) with enhanced migratory (CCR2) abilities, BUN and creatinine after UUO. AEC2-specific Mfn1^+/-/Mfn2^+/- deficiency induced UUO-mediated kidney fibrosis, frequency of kidney macrophages, and their profibrotic responses. Patients with IFTA had significantly increased circulating CCL17, IL-12p40, IL-12p70, and IL-6 levels. In patients with IFTA: a) circulating levels of IL-12p19 and IL-12p40 complex positively associated with osteopontin; b) glomerular filtration rate was negatively associated with plasma trefoil factor 3 and cystatin C; and c) urinary cystatin C was positively associated with CXCL10 and IL-6 levels.

Conclusion

During CKD, inflammatory macrophages negatively impact mitochondrial functions of AEC2, which then promote lung macrophage-derived inflammation. Lung macrophage-derived cytokines in turn aggravate kidney fibrosis by favoring migration of pro-inflammatory monocytes to the kidney in a bidirectional manner.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.20251r394w41