Miller, Mark

Dhaun, Neeraj

Angel, Souzana

other

2025-05-26T13:27:47Z

2025-05-26T13:27:47Z

2025-05-26

Exposure to ambient air pollution is associated with increased morbidity and mortality, contributing to an estimated 7–9 million premature deaths annually worldwide. While its effects on the respiratory system are well documented, epidemiological studies have also linked air pollution to diseases in extra-pulmonary organs, including the kidneys. Air pollution comprises a complex mix of gases, liquids and particulate matter (PM), with ultrafine particles (≤0.1 µm) posing significant risks due to their large surface area-to-mass ratio, capacity to carry surface chemicals and ability to reach remote organs. Diesel exhaust particles (DEP) are a major source of ultrafine PM in urban settings. I hypothesise that nanoparticles in diesel exhaust can reach and sequester in the kidney, compromising renal function through inflammation, oxidative stress and promoting renal vascular dysfunction. Particles can exert extra-pulmonary effects by entering the bloodstream and sequestering in distant organs. To investigate this pathway in the kidneys, mice were administered gold nanoparticles of various sizes (2, 3–4, 7–8, 14 and 40 nm) via pulmonary instillation/inhalation twice weekly for four weeks. Gold nanoparticles were chosen as they can be synthesised in broadly the same size as particles in diesel exhaust, gold is largely inert and there are a number of sensitive techniques to detect it. Using inductively coupled plasma mass spectrometry, gold was detected in the blood, urine and kidney in a size-dependent manner, with a statistical significance cutoff of <7 nm. The renal effects of acute exposure to DEP were investigated. Mice instilled with a single dose of reference material DEP (SRM 2975, NIST) exhibited pulmonary inflammation, evidenced by an increased total cell count (TCC) in the bronchoalveolar lavage fluid (BALF), primarily due to neutrophil infiltration. However, systemic inflammation was minimal, with only slight elevation in a few markers. DEP exposure did not upregulate kidney injury molecule-1 (KIM-1; early marker of kidney injury) or tumour necrosis factor alpha (TNF-α) expression in renal tissue. These results suggest that the dose and/or length of exposure may have been insufficient to induce renal effects. To further investigate, mice were exposed to DEP for four consecutive weeks (twice weekly), which resulted in pulmonary inflammation, evidenced by elevated BALF TCC, but had no impact on markers of systemic inflammation. Prolonged exposure did not affect kidney function, as indicated by unchanged mRNA expression of injury and inflammation markers in renal tissue, no changes in urinary excretion of KIM-1 and unaltered kidney morphology in histological assessments. The effect of DEP on renal vascular function was assessed in vitro using wire myography. Renal artery sections from healthy mice were exposed to DEP, either alone or with superoxide dismutase (SOD), in the myograph bath. DEP did not change the vascular reactivity to the adrenergic-dependent vasoconstrictor phenylephrine (PE) but caused a rightward shift in the dose-response curve of the endothelial-dependent vasodilator acetylcholine (ACh). A significant increase in the endothelial-independent vasodilator sodium nitroprusside (SNP) EC50 was noted following DEP addition, which was not reversed by the addition of SOD. To assess ex vivo effects, vascular reactivity of renal artery rings from mice chronically exposed to DEP was tested. While no overall changes were observed between the DEP and control groups, the ACh EC50 in the DEP group was significantly lower with a leftward shift in dose-response curve, indicating potential DEP-induced vascular hypersensitivity. Given the limited effects of DEP in healthy mice, a mouse model of hypertension-induced kidney injury was utilised. Mice were fed a high-salt diet (3% Na+) and implanted with osmotic minipumps delivering exogenous angiotensin II (500 ng/kg/min), while receiving DEP twice weekly. The study was terminated after two weeks due to mice suffering spontaneous aortic ruptures. DEP exposure did not induce systemic inflammation or alter renal mRNA expression of genes associated with kidney injury, inflammation or fibrosis. However, there was a trend towards increased renal transcript levels of the angiotensin receptor and oxidative stress-related genes (SOD3 and endothelial nitric oxide synthase-eNOS) in mice exposed to the combination of angiotensin II, a high-salt diet and DEP. In summary, despite nanoparticles having the ability to reach the kidney and to induce pulmonary inflammation, limited effects of DEP were seen in healthy mice. In a model of kidney injury DEP showed indications of oxidative stress and inflammation. Future studies should consider longer exposure periods of DEP, different sources of air pollution and other models of susceptibility to kidney injury. These results underscore the potential for air pollution to exacerbate underlying health conditions, emphasising the importance of stringent air quality regulations and targeted public health interventions.

https://hdl.handle.net/1842/43493

http://dx.doi.org/10.7488/era/6029

en

The University of Edinburgh

Angel, S., Eades, L.J., Sim, G. et al. New insights into the association of air pollution and kidney diseases by tracing gold nanoparticles with inductively coupled plasma mass spectrometry. Anal Bioanal Chem 416, 2683–2689 (2024). https://doi.org/10.1007/s00216-023-05105-8

kidney

kidney injury

air pollution

diesel exhaust particles

Effects of diesel exhaust particles on the kidney and renal vasculature

The effects of diesel exhaust particles on the kidney and renal vasculature

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy