Molecular Mechanisms of Apoptosis of Glomerular Podocytes in Diabetic Nephropathy
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Molecular Mechanisms of Apoptosis of Glomerular Podocytes in Diabetic Nephropathy A. O. Shpakova, * and E. V. Kaznacheyevab aSechenov
Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg, 194223 Russia bCytology Institute of Russian Academy of Sciences, St. Petersburg, 194064 Russia *e-mail: [email protected] Received November 29, 2019; revised January 13, 2020; accepted January 21, 2020
Abstract—Dysfunctions of glomerular podocytes and triggering of apoptotic processes in them are the main molecular causes of diabetic nephropathy and other kidney diseases. Pathogenetic factors causing these dysfunctions of podocytes are hyperglycemia, increased levels of advanced glycation end-products, oxidative stress, increased activity of inflammatory factors, and endoplasmic reticulum stress. These factors and their combinations result in the triggering of a number of intracellular signaling pathways that cause activation of apoptosis and reduce the survival of podocytes. Among these pathways are: (1) the Wnt/β-catenin pathway, which is activated by the Wnt-proteins when they bind to the complex of Frizzled receptors and LRP coreceptors; (2) the mTOR-dependent signaling pathway, including the mTORC1 and mTORC2 complexes, which are involved in the regulation of autophagy and endoplasmic reticulum stress and are regulated by various stimuli and effectors, in particular, the AMP-activated protein kinase; (3) the Rho/ROCK signaling pathway, including GTPases of the Rho family and Rho-associated protein kinase ROCK1; (4) calciumdependent signaling pathways triggered by an increase in the concentration of intracellular Ca2+, primarily through the activation of calcium channels of the TRPC family. The review provides a detailed analysis of the current state of knowledge about the molecular mechanisms responsible for the regulation of apoptotic processes in glomerular podocytes and also considers hormonal and other factors that regulate them both under normal conditions and under the conditions of lesions induced by hyperglycemia and diabetic nephropathy. Keywords: diabetic nephropathy, podocyte, apoptosis, calcium channel TRPC6, mTORC complex, Wnt/β-catenin pathway, GTPase of the Rho family DOI: 10.1134/S1990747820030058
INTRODUCTION Diabetic nephropathy (DN) with different characteristic forms of glomerulosclerosis is one of the most severe complications of diabetes mellitus (DM) and eventully leads to chronic kidney disease and high mortality among diabetic patients. The main pathogenic factors of DN are hyperglycemia, dislipidemia, intensification of inflammatory processes, arterial and glomerular hypertension; long-term hyperglycemia and the increased levels of advanced glycation endproducts induced by the latter play the key role here [1]. In kidneys, one of the targets of these factors are podocytes, differentiated epithelial cells localized in Bowman’s capsules, which enclose glomerular capillaries using the so-called “stalks”, leaving small slits for blood filtration. Th
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