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The largest city in Latin America is São Paulo, Brazil, where disorganized urbanization has had a negative impact on air quality and vehicle emissions are the main source of fine particulate matter (PM2.5). Epidemiological studies have linked PM2.5 exposure to an increased risk of chronic kidney disease. The mechanisms mediating the adverse health effects of PM2.5 include epigenetic changes, oxidative stress, and inflammation. The role of PM2.5 in acute kidney injury (AKI) has yet to be described. We hypothesized that PM2.5 exposure would aggravate renal ischemia/reperfusion (I/R) injury in mice.
In temperature-/humidity-controlled chambers within an ambient particle concentrator, mice were exposed to a concentrated PM2.5 stream or to high-efficiency particulate air-filtered clean air (CA). Mass concentrations of PM were measured with an airborne particulate monitor, and the target dose was 600 µg m−3/day (equivalent to the daily exposure in São Paulo). After 12 weeks, some mice underwent bilateral 30-min clamping of the kidney hila and subsequent reperfusion. Mice were divided into 4 groups: CA; PM2.5; CA+I/R; and PM2.5+I/R. All studies were performed 48 h after I/R.
Renal chemokines (Cxcl1, Ccl2, and Cxcl2) and cytokine Il1b showed increased gene expression in the PM2.5+I/R group, in which there was also significant activation of the cGAS-STING signaling pathway, including phosphorylation of interferon regulatory factor 3. The transcription of these factors was corroborated by the increased expression of the Ifnb and Cxcl10 genes. Renal gene expression of the profibrotic senescence-associated secretory phenotype components Tgfb, Pdgf, and Pai1 was higher in PM2.5+I/R mice than in CA+I/R mice. Data are mean ± SEM. Data are mean ± SEM.
Variable
Group
CA
PM2.5
CA+I/R
PM2.5+I/R
(n = 4)
(n = 7)
(n = 11)
(n = 14)
Creatinine clearance (mL/min)
0.67 ± 0.20
0.83 ± 0.33
0.76 ± 0.34
0.28 ± 0.26†
Fractional excretion of sodium (%)
0.13 ± 0.03
0.10 ± 0.03
0.12 ± 0.02
0.30 ± 0.07†
Urinary osmolality (mOsm/kg)
2045 ± 244
1949 ± 175
1764 ± 300
1106 ± 184†
Tubular injury score
0.00
1.0 ± 0.56
3.6 ± 0.64†
Klotho* (% positivity/HPF)
4.7 ± 0.8
4.8 ± 0.4
2.2 ± 0.15‡
1.1 ± 0.24†
F480*(% positivity/HPF)
0.71 ± 0.15
0.44 ± 0.04
0.83 ± 0.11
1.35 ± 0.16‡
Ki-67* (positive cells/HPF)
1.55 ± 0.41
1.32 ± 0.38
15.4 ± 7.7
30.6 ± 5.44‡
Ly6G* (positive cells/HPF)
0.67 ± 0.10
1.10 ± 0.20
12.19 ± 6.55‡
61.84 ± 11.29†
α-actin* (positive cells/HPF)
0.6 ± 0.1
1.1 ± 0.1
2.7 ± 0.6
7.4 ± 0.7§
P21 (positive cells/HPF)
0.2 ± 0.1
10 ± 5.0
43 ± 6.7
Ngal (relative to Tbp expression)‖
2.4 ± 0.7
4.2 ± 1.2
22.0 ± 9.0
115.2 ± 50.0¶
Ngal (ng/mL)**
55,181 ± 19,129
27,630 ± 8,129
2,218,345 ± 550,180
4,044,520 ± 546,777††
Data are mean ± SEM.
CA, clean air; PM2.5, fine particulate matter; I/R, ischemia/reperfusion; HPF, high-power field; Ngal, neutrophil gelatinase-associated lipocalin.
*Immunohistochemical analysis; †p < 0.05 vs. CA, PM2.5, and CA+I/R; ‡p < 0.05 vs. CA and PM2.5; §p < 0.001 vs. CA+I/R; ‖polymerase chain reaction with t-test; ¶p < 0.005 vs. CA+I/R; **enzyme-linked immunosorbent assay with t-test; ††p < 0.03 vs. CA+I/R.
Collectively, our findings suggest that exposure to PM2.5 worsens AKI-induced glomerular and tubular dysfunction, leading to reduced stress resilience, activation of aging mechanisms, and the appearance of hallmarks of fibrosis. Decreasing PM2.5 and implementing preventive strategies can prevent progression and improve outcomes in AKI (PM Kidney Consortium, FAPESP, NWO)