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Role and mechanism of C3a-C3a receptor in autosomal dominant polycystic kidney disease / 中华肾脏病杂志
Chinese Journal of Nephrology ; (12): 454-462, 2020.
Artigo em Chinês | WPRIM | ID: wpr-870981
ABSTRACT

Objective:

To explore the role and mechanism of C3a-C3a receptor (C3aR) in the progression of autosomal dominant polycystic kidney disease (ADPKD).

Methods:

Renal tissues of ADPKD patients and PKD1 knockout mice were collected. Then the expression of C3a-C3aR, Ki67 and F4/80 in renal tissues was observed. Macrophages were stimulated with lipopolysaccharide (LPS) and interleukin 4 respectively. The expression of C3aR, TNF-α, typing markers and related signal pathway proteins was detected in each group. PKD1 knockout mice were treated with C3aR inhibitor SB290157 (1 mg/kg). Renal pathology, cyst-related indicators and renal function were observed.

Results:

The expression of C3a and C3aR in ADPKD was up-regulated (both P<0.05); C3aR and F4/80 were co-located in the kidney of polycystic kidney disease (PKD) mice, indicating that C3aR was mainly expressed on membrane of macrophages. In vitro, the expression of C3aR was up-regulated in M1 macrophages ( P<0.05). After the stimulation of C3a, the expression of iNOS, TNF-α and IL-6 mRNA in M1 macrophages were up-regulated (all P<0.05), as well as the secretion of TNF-α, indicating that C3a not only affected the expression of inflammatory factors of M1 macrophages, but also affected the inflammatory microenvironment. In addition, C3a significantly activated Akt in M1 macrophages ( P<0.05). Compared with the control group, the treatment group showed a decrease in C3a-C3aR as well as serum BUN, Scr, cyst index, and two kidneys weight/body weight (2KW/BW) (all P<0.05), and ADPKD related pathway protein expression such as p-ERK and p-P65 was significantly down-regulated (all P<0.05).

Conclusions:

The increased C3a in polycystic kidney tissue causes infiltration and activation of macrophages through C3aR, and then promotes ADPKD progression. The mechanism may be mediated by Akt activation and increased TNF-α production. C3aR antagonist is a potential research direction in the treatment of ADPKD.
Texto completo: DisponíveL Índice: WPRIM (Pacífico Ocidental) Idioma: Chinês Revista: Chinese Journal of Nephrology Ano de publicação: 2020 Tipo de documento: Artigo

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Texto completo: DisponíveL Índice: WPRIM (Pacífico Ocidental) Idioma: Chinês Revista: Chinese Journal of Nephrology Ano de publicação: 2020 Tipo de documento: Artigo