MAGI2 ameliorates podocyte apoptosis of diabetic kidney disease through communication with TGF-β-Smad3/nephrin pathway.

Abstract

Podocytes, the key component of the glomerular filtration barrier (GFB), are gradually lost during the progression of diabetic kidney disease (DKD), severely compromising kidney functionality. The molecular mechanisms regulating the survival of podocytes in DKD are incompletely understood. Here, we show that membrane-associated guanylate kinase inverted 2 (MAGI2) is specifically expressed in renal podocytes, and promotes podocyte survival in DKD. We found that MAGI2 expression was downregulated in podocytes cultured with high-glucose in vitro, and in kidneys of db/db mice as well as DKD patients. Conversely, we found enforced expression of MAGI2 via AAV transduction protected podocytes from apoptosis, with concomitant improvement of renal functions. Mechanistically, we found that MAGI2 deficiency induced by high glucose levels activates TGF-β signaling to decrease the expression of anti-apoptotic proteins. These results indicate that MAGI2 protects podocytes from cell death, and can be harnessed therapeutically to improve renal function in diabetic kidney disease.

• Authors: Tingli Wang, Chen Li, Xiaofei Wang, Fang Liu
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 37 Issue 12 Pg. e23305 (12 2023) ISSN: 1530-6860 [Electronic] United States
• PMID: 37950637 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

Chemical References

• Adaptor Proteins, Signal Transducing
• Glucose
• Guanylate Kinases
• MAGI2 protein, human
• nephrin
• Transforming Growth Factor beta
• Magi2 protein, mouse

Topics

• Animals
• Humans
• Mice
• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Apoptosis
• Communication
• Diabetes Mellitus (metabolism)
• Diabetic Nephropathies (metabolism)
• Glucose (metabolism)
• Guanylate Kinases (genetics)
• Podocytes (metabolism)
• Transforming Growth Factor beta (metabolism)