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Air pollution is a significant but often overlooked factor in the development of chronic kidney disease. It can start affecting kidney health already during pregnancy. Exposure to air pollution during early life can hinder organ growth, leading to premature birth, low birth weight, hypertension and decreased renal function later in life. Combustion-derived particles, such as soot, are one of the most hazardous components of air pollution. Soot contains unregulated Ultrafine particles (UFPs: <100nm), which exert higher toxicity than larger particles, have significant renal clearance and represent a growing concern for public health. UFPs can cross the placenta and reach fetal organs during gestation. Here, we aim to investigate the impact of UFPs during early life on kidney development and resilience.
We exposed pregnant mice and offspring (exclusively during lactation) to UFPs or filtered air, via inhalation. Animals were sacrificed at the end of lactation period (Postnatal day 21) resulting in 4 groups (control, prenatal, postnatal and pre+postnatal exposure). Kidneys were harvested and processed for histology, targeted assay, immunofluorescence and Transmission Electron Microscopy (TEM). In vitro, we stimulated iPSCs-derived kidney organoids with Printex 90 (a proxy for UFPs), followed by hypoxia/re-oxygenation. Organoids were harvested for RT-PCR.
Using the framework for large-scale histomorphometry, we observed a decreased cortical tubular area and diameter, and increased distance among cortical tubules, in the pre+postnatal group. Through the application of immunofluorescence techniques, we have discerned a significant repositioning of the brush border in proximal tubular cells (pTECs) within the pre+postnatal group. The same group showed decreased renal Nicotinamide-adenine-dinucleotide (NAD+) pool, an essential cofactor in pTECs mitochondrial function. TEM analysis of pTECs revealed a reduction in mitochondria number, volume and altered cristae structure, in the pre+postnatal group. This was associated with a decline in glycolysis, measured by PKM2 IHC. In vitro, Printex90-stimulated kidney organoids displayed an increased expression of pTECs damage markers KIM1 and CD44, following hypoxia/re-oxygenation
Exposure to UFPs during gestation and lactation revealed poor development of pTECs, possibly due to mitochondrial dysfunction. Kidney organoids experiments demonstrated also a decreased tubular resilience in the UFP-treated group. Altogether our results suggest that early life exposure to UFPs may induce developmental programming of kidney disease with long-term effects later in life