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. 2021 Nov 26;135(22):2575-2588.
doi: 10.1042/CS20210802.

Paternal long-term PM2.5 exposure causes hypertension via increased renal AT1R expression and function in male offspring

Cuimei Hu #  1   2 , Yu Tao #  1   2 , Yi Deng  3 , Qi Cai  4 , Hongmei Ren  1   2 , Cheng Yu  4 , Shuo Zheng  1   2 , Jian Yang  5 , Chunyu Zeng  1   2   6   7
Affiliations

Paternal long-term PM2.5 exposure causes hypertension via increased renal AT1R expression and function in male offspring

Cuimei Hu et al. Clin Sci (Lond). .

Abstract

Maternal exposure to fine particulate matter (PM2.5) causes hypertension in offspring. However, paternal contribution of PM2.5 exposure to hypertension in offspring remains unknown. In the present study, male Sprague-Dawley rats were treated with PM2.5 suspension (10 mg/ml) for 12 weeks and/or fed with tap water containing an antioxidant tempol (1 mM/L) for 16 weeks. The blood pressure, 24 h-urine volume and sodium excretion were determined in male offspring. The offspring were also administrated with losartan (20 mg/kg/d) for 4 weeks. The expressions of angiotensin II type 1 receptor (AT1R) and G-protein-coupled receptor kinase type 4 (GRK4) were determined by qRT-PCR and immunoblotting. We found that long-term PM2.5 exposure to paternal rats caused hypertension and impaired urine volume and sodium excretion in male offspring. Both the mRNA and protein expression of GRK4 and its downstream target AT1R were increased in offspring of PM2.5-exposed paternal rats, which was reflected in its function because treatment with losartan, an AT1R antagonist, decreased the blood pressure and increased urine volume and sodium excretion. In addition, the oxidative stress level was increased in PM2.5-treated paternal rats. Administration with tempol in paternal rats restored the increased blood pressure and decreased urine volume and sodium excretion in the offspring of PM2.5-exposed paternal rats. Treatment with tempol in paternal rats also reversed the increased expressions of AT1R and GRK4 in the kidney of their offspring. We suggest that paternal PM2.5 exposure causes hypertension in offspring. The mechanism may be involved that paternal PM2.5 exposure-associated oxidative stress induces the elevated renal GRK4 level, leading to the enhanced AT1R expression and its-mediated sodium retention, consequently causes hypertension in male offspring.

Keywords: Developmental programing; Hypertension; Kidney; PM2.5; Paternal exposure.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Flow diagram 1
Flow diagram 1. The diagram of the animal experiment set 1
Control offspring: the vehicle-treated paternal offspring treated with saline; control+losartan offspring: the vehicle-treated paternal offspring treated with losartan (20 mg/kg/d, 4 weeks, once a day); PM2.5 offspring: the PM2.5-exposed paternal offspring treated with saline; PM2.5+losartan offspring: the PM2.5-exposed paternal offspring treated with losartan (20 mg/kg/d, 4 weeks, once a day).
Flow diagram 2
Flow diagram 2. The diagram of the animal experiment set 2
Control offspring: offspring of paternal rats treated with vehicle and PBS; Control+ tempol offspring: offspring of paternal rats treated with tempol (1 mM/L, 16 weeks); PM2.5 offspring: offspring of paternal rats treated with PM2.5; PM2.5+tempol offspring: offspring of paternal rats treated with both PM2.5 and tempol (1 mM/L, 16 weeks).
Figure 1
Figure 1. Lung histology from control- and PM2.5-exposed SD rats
Representative light microscopy sections of lung tissues from vehicle- and PM2.5-treated SD rats. Unabsorbed particles in the alveoli are presented in different power images. Red arrow means fine particulate matter deposition; magnification 400×.
Figure 2
Figure 2. Effect of PM2.5 exposure on the regulation of blood pressure and sodium excretion in SD rats
(A and B) Systolic blood pressure (SBP) (A) and diastolic blood pressure (DBP) (B) were measured by the tail-cuff method after 12-weeks PM2.5 exposure (A, two-tailed, unpaired t test with Welch’s correction, *P < 0.05 vs. control, n = 10; B, two-tailed, unpaired t test, *P < 0.05 vs. control, n = 10). (C and D) 24 h urine volume (C) and sodium excretion (D) were determined in the control and PM2.5-exposed SD rats after 12-week PM2.5 exposure (C and D): two-tailed, unpaired t test, *P < 0.05 vs. control, n = 10). (E) Differences of the SBP among vehicle- (control) and PM2.5-exposed SD rats aged 6-, 9-, 12-, 15- and 18-week-old (one-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. control, n = 10). (F) Weights of vehicle- (control) and PM2.5-exposed SD rats (two-tailed, unpaired t test, ns. P > 0.05 vs. control, n = 10).
Figure 3
Figure 3. Effects of paternal PM2.5 exposure on the regulation of blood pressure and renal functions in offspring
(A) Systolic blood pressure (SBP) in the different weeks old PM2.5 offspring (one-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. control offspring, n = 8). (B and C) 24 h urine volume (B) and sodium excretion (C) in the 12-week-old PM2.5 offspring (B and C, two-tailed, unpaired t test, *P < 0.05 vs. control offspring, n = 8). (D) Renal histopathology was examined by H&E staining in the 12-week-old PM2.5 offspring; magnification 200×. Control offspring: offspring of vehicle-exposed paternal SD rats; PM2.5 offspring: offspring of PM2.5-exposed paternal rats.
Figure 4
Figure 4. AT1R and GRK4 expression and function in the offspring of PM2.5-exposed paternal rats
(A and B) The mRNA (A) and protein expression (B) of AT1R were determined by qt-PCR and immunoblotting in the 12-week-old PM2.5 offspring. AT1R mRNA level was normalized using GAPDH. The protein expression of AT1R was normalized using tubulin expression (A and B, two-tailed, unpaired t test, *P < 0.05 vs. control, n = 6). (C) Effect of losartan (20 mg/kg/d, 4 weeks) on the systolic blood pressure (SBP) in the PM2.5 offspring (two-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. P- offspring +losartan, n = 8; #P < 0.05 vs. C-offspring, n = 8). (D and E) Effect of losartan (20 mg/kg/d, 4 weeks) on the 24 h urine volume (D) and sodium excretion (E) in the PM2.5 offspring. (D and E, two-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. C-offspring, n = 8; #P < 0.05 vs. P-offspring, n = 8). (F and G) The mRNA (F) and protein expression (G) of GRK4 were determined by qt-PCR and immunoblotting in the 12-week-old PM2.5 offspring. AT1R mRNA level was normalized using GAPDH. The protein expressions of GRK4 were normalized using tubulin expression (F and G, two-tailed, unpaired t test, *P < 0.05 vs. C-offspring, n = 6). Control offspring (C or C-offspring): offspring of vehicle-exposed paternal SD rats; PM2.5 offspring (P or P-offspring): offspring of PM2.5-exposed paternal rats.
Figure 5
Figure 5. Role of oxidative stress in the paternal PM2.5 exposure-induced hypertension in offspring
(A and B) Renal MDA (A) and SOD (B) levels were measured in vehicle (control)- and PM2.5-treated paternal SD rats (A and B, two-tailed, unpaired t test, *P < 0.05 vs. control, n = 6). (C–E) Systolic blood pressure (SBP) (C), 24 h urine volume (D) and sodium excretion (E) were determined in the 12-week-old offspring of 12 weeks PM2.5-exposed- and 16 weeks tempol-treated paternal rats (C–E: two-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. control offspring, n = 8; #P < 0.05 vs. PM2.5 offspring, n = 8). (F and G) Protein expressions of AT1R (F) and GRK4 (G) were determined by Western blot in the kidney from the 12-week-old offspring of 12 weeks PM2.5-exposed- and 16 weeks tempol-treated paternal rats. AT1R or GRK4 protein expression was normalized using GAPDH expression (F and G, two-way ANOVA with Tukey’s post hoc test, *P < 0.05 vs. control, n = 6; #P < 0.05 vs. PM2.5, n = 6). Control: vehicle-exposed paternal rats; PM2.5: PM2.5-exposed-paternal rats; C-offspring: offspring of vehicle-exposed and vehicle-treated paternal rats; P-offspring: offspring of PM2.5-exposed and vehicle-treated paternal rats; C+Tempol-offspring: offspring of vehicle-exposed- and tempol-treated paternal rats; P+Tempol-offspring: offspring of PM2.5-exposed- and tempol-treated paternal rats.
Figure 6
Figure 6. Schematic diagram of the effect of paternal long-term PM2.5 exposure on renal AT1R function and blood pressure in offspring
Paternal PM2.5 exposure, via increased oxidative stress, elevates renal expressions of GRK4 and its downstream target AT1R in their offspring, which leads to the enhanced AT1R-mediated urinary sodium retention, and ultimately hypertension.
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References

    1. Virani S.S., Alonso A., Aparicio H.J., Benjamin E.J., Bittencourt M.S., Callaway C.W.et al. . (2021) Heart disease and stroke statistics-2021 update: a report from the American Heart Association. Circulation 143, e254–e743 10.1161/CIR.0000000000000950 - DOI - PubMed
    1. Kawarazaki W. and Fujita T. (2021) Kidney and epigenetic mechanisms of salt-sensitive hypertension. Nat. Rev. Nephrol. 17, 350–363 10.1038/s41581-021-00399-2 - DOI - PubMed
    1. Seidel E. and Scholl U.I. (2017) Genetic mechanisms of human hypertension and their implications for blood pressure physiology. Physiol. Genomics 49, 630–652 10.1152/physiolgenomics.00032.2017 - DOI - PubMed
    1. Fuks K.B., Weinmayr G., Basagaña X., Gruzieva O., Hampel R., Oftedal B.et al. . (2017) Long-term exposure to ambient air pollution and traffic noise and incident hypertension in seven cohorts of the European study of cohorts for air pollution effects (ESCAPE). Eur. Heart J. 38, 983–990 10.1093/eurheartj/ehw413 - DOI - PubMed
    1. Arima Y. and Fukuoka H. (2020) Developmental origins of health and disease theory in cardiology. J. Cardiol. 76, 14–17 10.1016/j.jjcc.2020.02.003 - DOI - PubMed

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