Reduced Glomerular Filtration in Diabetes Is Attributable to Loss of Density and Increased Resistance of Glomerular Endothelial Cell Fenestrations

Natalie C. Finch; Sarah S. Fawaz; Chris R. Neal; Matthew J. Butler; Vivian K. Lee; Andrew J. Salmon; Abigail C. Lay; Megan Stevens; Lusyan Dayalan; Hamid Band; Harry H. Mellor; Steven J. Harper; David T. Shima; Gavin I. Welsh; Rebecca R. Foster; Simon C. Satchell

doi:10.1681/ASN.2021030294

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

We propose a novel mechanism underlying loss of renal filtration function from studying glomerular endothelial cell (GEnC) fenestrae in human diabetic kidney tissue and in a mouse model of diabetes. Diaphragmed fenestrae may provide structural resistance to filtration. We hypothesize that EHD3 is a key regulator of GEnC fenestrations, and its glomerular expression is lost in diabetes. This study establishes the critical role of GEnC fenestrations in renal filtration function and suggests a key regulator, potentially paving the way for development of targeted therapies to restore fenestrae and thus filtration function in kidney disease.

Abstract

Background Glomerular endothelial cell (GEnC) fenestrations are recognized as an essential component of the glomerular filtration barrier, yet little is known about how they are regulated and their role in disease.

Methods We comprehensively characterized GEnC fenestral and functional renal filtration changes including measurement of glomerular K_f and GFR in diabetic mice (BTBR ob⁻/ob⁻). We also examined and compared human samples. We evaluated Eps homology domain protein-3 (EHD3) and its association with GEnC fenestrations in diabetes in disease samples and further explored its role as a potential regulator of fenestrations in an in vitro model of fenestration formation using b.End5 cells.

Results Loss of GEnC fenestration density was associated with decreased filtration function in diabetic nephropathy. We identified increased diaphragmed fenestrations in diabetes, which are posited to increase resistance to filtration and further contribute to decreased GFR. We identified decreased glomerular EHD3 expression in diabetes, which was significantly correlated with decreased fenestration density. Reduced fenestrations in EHD3 knockdown b.End5 cells in vitro further suggested a mechanistic role for EHD3 in fenestration formation.

Conclusions This study demonstrates the critical role of GEnC fenestrations in renal filtration function and suggests EHD3 may be a key regulator, loss of which may contribute to declining glomerular filtration function through aberrant GEnC fenestration regulation. This points to EHD3 as a novel therapeutic target to restore filtration function in 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.