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ZHANG He-ping, LIU Jia-li, TANG Jin-cheng, XIE Rong, YANG Kun, ZHANG Jie, FENG Jiang-chao. Inhibition of angiotensin Ⅱ type 1 receptor on Renal Fibrosis and Podocyte Damage in AngiotensinⅡ-induced Hypertensive Nephropathy[J]. Journal of Clinical Nephrology, 2022, 22(4): 315-322. DOI: 10.3969/j.issn.1671-2390.2022.04.009
Citation: ZHANG He-ping, LIU Jia-li, TANG Jin-cheng, XIE Rong, YANG Kun, ZHANG Jie, FENG Jiang-chao. Inhibition of angiotensin Ⅱ type 1 receptor on Renal Fibrosis and Podocyte Damage in AngiotensinⅡ-induced Hypertensive Nephropathy[J]. Journal of Clinical Nephrology, 2022, 22(4): 315-322. DOI: 10.3969/j.issn.1671-2390.2022.04.009

Inhibition of angiotensin Ⅱ type 1 receptor on Renal Fibrosis and Podocyte Damage in AngiotensinⅡ-induced Hypertensive Nephropathy

Funds: 

Research Project Fund of Sichuan Provincial Health Commission(19ZD006)

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  • Received Date: July 08, 2021
  • Available Online: May 11, 2023
  • Published Date: June 27, 2023
  • Objective To explore the effect of targeted inhibition of angiotensin Ⅱ type 1 receptor(AGTR1)on renal fibrosis and podocyte damage in angiotensin Ⅱ-induced hypertensive nephropathy.Methods The murine experimental groups include normal control group,normal saline group,model group and drug group(n=10 each). Normal control group was not treated,normal saline group underwent unilateral nephrectomy plus microosmotic pump infusion of normal saline,model group unilateral nephrectomy plus micro-osmotic pump perfusion with angiotensin Ⅱ,drug group unilateral nephrectomy plus an intraperitoneal injection of 50 mg/kg of Losartan 30 min before perfusion of angiotensin Ⅱ with a micro-osmotic pump. Blood pressures were measured for each group at pre-modeling and 2/4 weeks postmodeling. At 4 weeks post-modeling,enzyme-linked immunosorbent assay was employed for detecting24 h urinary protein(24 h UP),serum creatinine(Scr)and urea nitrogen(BUN);hematoxylin-eosin(HE)staining for observing the pathological morphology of kidney tissue;Masson staining for detecting renal tissue fibrosis,observing the ultrastructural changes of podocytes with transmission electron microscope,immunofluorescent staining for detecting the expression of nephrin in podocytes of renal tissue,Western blot for detecting the expressions of α-smooth muscle actin(α-SMA),type Ⅰ/Ⅲ collagen(collagen-Ⅰ/Ⅲ),nephrin,podocin and synaptopodin.Results Compared with normal control group,blood pressure rose after modeling[modeling for 2 weeks:(148.92±12.56) mmHg vs(109.18±9.43)mmHg;modeling for 4 weeks:(150.92±13.74)mmHg vs(117.68±10.73)mmHg,1 mmHg=0.133kPa]and 24 h UP[(2.02±0.18)mg/24h vs(3.88±0.34)mg/24h vs(0.37±0.02)mg/24h],Scr[(11.34±0.97)μmol/L vs(13.92±1.16)μmol/L vs(9.18±0.87)μmol/L]and BUN[(11.34±1.09) mmol/L vs(14.55±1.30) mmol/L vs(7.71±0.73) mmol/L] spiked in normal saline and model groups,renal tubules appeared atrophic and necrotic with vacuolar degeneration,and epithelial cells sloughed off,heavy infiltrate of inflammatory cells,accompanied by obvious fibrosis,podocyte foot process thickened and merged,slit membrane disappeared,fluorescent intensity of nephrin declined,protein expression levels of α-SMA and collagen-Ⅰ/Ⅲ spiked while protein expression levels of nephrin,podocin and synaptopodin declined(P<0.01). Compared with model group,blood pressure of drug group dropped[2 weeks of modeling:(125.08±10.79)mmHg vs(148.92±12.56)mmHg;4 weeks of modeling:(122.78±10.07) mmHg vs(150.92±13.74) mmHg],24 h UP[(1.25±0.11) mg/24h vs(3.88±0.34)mg/24h],Scr[(10.33±0.84)μmol/L vs(13.92±1.16)μmol/L]and BUN[(8.96±0.81)mmol/L vs(14.55±1.30)mmol/L]decreased,renal tubular atrophy,necrosis and vacuolar degeneration were alleviated,minimal infiltration of inflammatory cell,degree of fibrosis lessened,foot process thickened and fusion phenomenon improved. At the same time,fluorescent intensity of nephrin increased,rotein expression levels of α-SMA and collagen-Ⅰ/Ⅲ dropped while protein expression levels of nephrin,podocin and synaptopodin spiked(P<0.01).Conclusion Inhibition of AGTR1 may reduce renal fibrosis in a murine model of hypertensive nephropathy induced by angiotensinⅡand at the same time reduce podocyte damage.
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