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

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: AEC2but 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 (Ly6Chigh, 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 - NIDDK Support, NIDDK Support