Complement C3a and C3a Receptor Activation Mediates Podocyte Injuries in the Mechanism of Primary Membranous Nephropathy

Shuang Gao; Zhao Cui; Ming-hui Zhao

doi:10.1681/ASN.2021101384

This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.

Visual Abstract

Significance Statement

Membranous nephropathy (MN) is the leading cause of adult nephrotic syndrome, in which the complement system is highly activated. This paper describes the discovery that the C3a/C3aR pathway is a crucial effector of complement-mediated podocyte injuries in MN. Levels of plasma C3a and glomerular C3aR are elevated in patients with MN compared with healthy controls, and are associated with severity and prognosis. In vitro, C3a from MN patients’ plasma damages the physiologic function and cellular activity of podocytes, which C3aR antagonists block. In vivo, C3aR antagonists can also attenuate renal injuries of Heymann nephritis (a classic disease model of MN) rats. Collectively, C3aR blockade may be a potentially viable treatment for this disease.

Abstract

Background The complement system is highly activated in primary membranous nephropathy (MN). Identifying the complement components that damage podocytes has important therapeutic implications. This study investigated the role of C3a and the C3a receptor (C3aR) in the pathogenesis of MN.

Methods C3aR expression in kidneys and circulating levels of C3a of MN patients were examined. Human podocyte damage was assessed after exposure to MN plasma +/− C3aR blockade (SB290157, JR14a). C3aR antagonists were administered to rats with Heymann nephritis on day 0 or after proteinuria. Clinical and pathologic parameters, specific IgG and complement activation, and podocyte injuries were then assessed.

Results In the glomeruli, C3aR staining merged well with podocin. Overexpression of C3aR correlated positively with proteinuria, serum creatinine, and no-response to treatments. Human podocytes exposed to MN plasma showed increased expression of PLA2R, C3aR, and Wnt3/β-catenin, reduced expression of synaptopodin and migration function, downregulated Bcl-2, and decreased cell viability. C3aR antagonists could block these effects. In Heymann nephritis rats, C3aR blockade attenuated proteinuria, electron-dense deposition, foot process width, and glomerular basement membrane thickening in glomeruli. The increased plasma C3a levels and overexpression of C3aR were also alleviated. Specific, but not total, IgG levels decreased, with less deposition of rat IgG in glomeruli and subsequent reduction of C1q, factor B, and C5b-9.

Conclusion C3a anaphylatoxin is a crucial effector of complement-mediated podocyte damage in MN. The C3aR antagonist may be a potentially viable treatment for this disease.

View Full Text

If you are:

an ASN member, select the "ASN Member" login button.
an individual subscriber, login with you User Name and Password.
an Institutional user, select the Institution option where you will be presented with a list of Shibboleth federations. If you do not see your federation, contact publications@asn-online.org.

Log in through your institution

Purchase access

Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$34.00

In order to get access to the article, you must have an account. If you have an account, enter your user name and password into the boxes above. If you do not have an account, follow the instructions below to create one. Once you have purchased the article, you will have access to it for 24 hours.

Steps for Creating an Account:

Click the "Purchase Access" button. The page will redisplay with the following message at the top of the screen. In the message, click to create an account.

When you create the account, you will be asked to register a user name, email address and you will need to create a password that is at least eight characters in length. You do not need an ASN Member number to complete the form. As you move through the registration page, you will have to verify you are a person by completing a Captcha request. Lastly, your first and last name will be required.

Once your information is successfully saved, the system will redisplay the home page of the journal. From there, navigate back to the article to purchase. Select the article and at the bottom of the page, use the credentials you just created to login. The article will be added to your shopping cart. You can continue to navigate across JASN and CJASN adding to your cart from both journals. When you are ready to complete your purchse, select the Shopping Cart from the upper right hand corner of the page and follow the onscreen instructions.