Fcγ Receptor Deficiency Attenuates Diabetic Nephropathy

• Published in: Journal of the American Society of Nephrology 2012-09, Vol.23 (9), p.1518-1527
• Main Authors: LOPEZ-PARRA, Virginia, MALLAVIA, Benat, LOPEZ-FRANCO, Oscar, ORTIZ-MUNOZ, Guadalupe, OGUIZA, Ainhoa, RECIO, Carlota, BLANCO, Julia, NIMMERJAHN, Falk, EGIDO, Jesus, GOMEZ-GUERRERO, Carmen
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Albuminuria - epidemiology; Animals; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Associated diseases and complications; Basic Research; Biological and medical sciences; Collagen - metabolism; Diabetes Mellitus, Experimental - chemically induced; Diabetes Mellitus, Experimental - complications; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - etiology; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - prevention & control; Disease Models, Animal; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Hypertrophy - epidemiology; Incidence; Kidney - metabolism; Kidney - pathology; Kidneys; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Nephrology. Urinary tract diseases; Receptors, IgG - deficiency; Receptors, IgG - genetics; Signal Transduction - physiology; Streptozocin - adverse effects; Urinary system involvement in other diseases. Miscellaneous
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2011080822

Among patients with diabetes, increased production of immunoglobulins against proteins modified by diabetes is associated with proteinuria and cardiovascular risk, suggesting that immune mechanisms may contribute to the development of diabetes complications, such as nephropathy. We investigated the contribution of IgG Fcγ receptors to diabetic renal injury in hyperglycemic, hypercholesterolemic mice. We used streptozotocin to induce diabetes in apolipoprotein E-deficient mice and in mice deficient in both apolipoprotein E and γ-chain, the common subunit of activating Fcγ receptors. After 15 weeks, the mice lacking Fcγ receptors had significantly less albuminuria and renal hypertrophy, despite similar degrees of hyperglycemia and hypercholesterolemia, immunoglobulin production, and glomerular immune deposits. Moreover, diabetic Fcγ receptor-deficient mice had less mesangial matrix expansion, inflammatory cell infiltration, and collagen and α-smooth muscle actin content in their kidneys. Accordingly, expression of genes involved in leukocyte infiltration, fibrosis, and oxidative stress was significantly reduced in diabetic kidneys and in mesangial cells cultured from Fcγ receptor-deficient mice. In summary, preventing the activation of Fcγ receptors alleviates renal hypertrophy, inflammation, and fibrosis in hypercholesterolemic mice with diabetes, suggesting that modulating Fcγ receptor signaling may be renoprotective in diabetic nephropathy.