Evolution in the understanding of idiopathic membranous nephropathy pathogenesis: from experimental models to the clinic

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Abstract

Membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. This review describes a 60-year history of MN study and represents an evolution in the understanding of its pathogenesis from experimental models to the clinic. Due to the development in 1959 of an MN animal model (active and passive Heymann's nephritis) the renal autoantigen podocyte-related protein megalin was identified. Experimental studies confirmed that the immune deposits consisting of megalin with circulating antimegalin antibodies are formed in situ. That leads to the complement activation providing with the membrane attack complex formation in the subepithelial space which causes a  sub-lethal podocyte injury with a  reorganization of their actin cytoskeleton and a  dissociation of slit diaphragm proteins. As the result, the permeability of the filtration barrier increases leading to the proteinuria. Thus, the understanding of an idiopathic MN pathogenesis evolved from an immune complex-mediated damage into a podocytopathy so the pathway for the other podocyte-related antigens search was opened. Mechanisms of podocytes damage were considered to be the leading ones in the human idiopathic MN development. Nevertheless, the searching for antigenic targets different from the megalin was continued for many years, as human podocytes do not express this protein. In the first decade of the 21st century such autoantigens as neutral endopeptidase, M-type phospholipase A2 receptor, and thrombospondin type-1 domain-containing 7A were identified. Furthermore, the leading role of autoantibodies directed against these podocyte targets was confirmed. New knowledge formed the basis for modern diagnostics and treatment methods of MN. 

About the authors

I. N. Bobkova

I.M. Sechenov First Moscow State Medical University

Author for correspondence.
Email: irbo.mma@mail.ru

MD, PhD, Professor, Chair of Internal Medicine and Occupational Medicine, Faculty of Preventive Medicine

11а–23 Gagarina ul., Krasnoznamensk, Moscow Region, Moscow, 143090

Tel.: +7 (917) 559 71 43

8/2 Trubetskaya ul., 119991

Russian Federation

P. A. Каkhsurueva

I.M. Sechenov First Moscow State Medical University

Email: fake@neicon.ru

MD, Postgraduate Student, Chair of Internal Medicine and Occupational Medicine, Faculty of Preventive Medicine

8/2 Trubetskaya ul., Moscow, 119991

Russian Federation

E. V. Stavrovskaya

I.M. Sechenov First Moscow State Medical University

Email: fake@neicon.ru

MD, PhD, Associate Professor, Chair of Internal Medicine and Occupational Medicine, Faculty of Preventive Medicine

8/2 Trubetskaya ul., Moscow, 119991

Russian Federation

E. E. Filatova

I.M. Sechenov First Moscow State Medical University

Email: fake@neicon.ru

Student

8/2 Trubetskaya ul., Moscow, 119991

Russian Federation

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