Air Pollution Accelerates Aging of the Kidneys, Lungs, and Heart

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Background: Air pollution affects multiple organs, causing approximately 4.2 million premature deaths worldwide each year. The respiratory system is especially affected by exposure to fine particulate matter (PM2.5), which has also been correlated with cardiovascular disease. We have previously shown that PM2.5 aggravates ischemia/reperfusion injury-induced AKI in mice, as well as being associated with greater albuminuria and a higher risk of incident CKD. Methods: Eight-week-old mice were housed for 18 months in exposome chambers in São Paulo, Brazil. The chambers allowed the entry of unfiltered or HEPA-filtered air (UFA and HFA, respectively). Kidneys, hearts and lungs were biopsied, and kidney specimens were assessed with a pathomics-based deep learning model to evaluate changes in morphology. To investigate molecular changes, we performed bulk RNA sequencing, as well as lipidomic/metabolomic profiling to examine gene expression, cellular lipid composition and small-molecule metabolites. At age 12 months, mice underwent echocardiography. Results: Serum cystatin C was higher (i.e., renal function was lower) in the UFA group (0.76±0.09 vs. 0.90±0.04 ng/mL, P<0.05). UFA group mice developed glomerular hypertrophy, glomerulosclerosis, tubular dilation and arterial wall thickening, indicating structural remodeling, as well as dysregulation of genes associated with fatty acid metabolism, including Slc27a2, Cd36, Pparα, Cpt1a, Fatp4 and Cpt1c—key hallmarks of kidney disease. In the UFA group, there were elevated triglyceride species; higher levels of glycolipids, such as Hex2Cer; accumulation of acetyl-CoA, a key product of lipid metabolism; higher leukocyte counts in the blood (P<0.05); and higher CD43+ cell counts in the lungs (P<0.05). UFA group mice had greater systolic left ventricular internal diameters and E/A ratios (P<0.05 for both), which can indicate diastolic dysfunction. At age 18 months, heart weights were greater in UFA group mice (P<0.05), as were the right ventricle, right septum and extent of fibrosis. Conclusion: Lifelong PM2.5 exposure induces structural kidney damage and reprograms renal lipid and energy metabolisms, as well as inducing inflammation, thus accelerating renal, pulmonary and cardiac aging. (Support by FAPESP) Funding: Government Support – Non-U.S.

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