Abstract
Two coding sequence variants (G1 and G2) of Apolipoprotein L1 (APOL1) gene have been implicated as a higher risk factor for chronic kidney diseases (CKD) in African Americans when compared with European Americans. Previous studies have suggested that the APOL1 G1 and G2 variant proteins are more toxic to kidney cells than the wild-type APOL1 G0, but the underlying mechanisms are poorly understood. To determine whether endoplasmic reticulum (ER) stress contributes to podocyte toxicity, we generated human podocytes (HPs) that stably overexpressed APOL1 G0, G1, or G2 (Vec/HPs, G0/HPs, G1/HPs, and G2/HPs). Propidium iodide staining showed that HP overexpressing the APOL1 G1 or G2 variant exhibited a higher rate of necrosis when compared with those overexpressing the wild-type G0 counterpart. Consistently, the expression levels of nephrin and podocin proteins were significantly decreased in the G1- or G2-overexpressing cells despite the maintenance of their mRNA expressions levels. In contrast, the expression of the 78-kDa glucose-regulated protein ((GRP78), also known as the binding Ig protein, BiP) and the phosphorylation of the eukaryotic translation initiation factor 1 (eIF1) were significantly elevated in the G1/HPs and G2/HPs, suggesting a possible occurrence of ER stress in these cells. Furthermore, ER stress inhibitors not only restored nephrin protein expression, but also provided protection against necrosis in G1/HPs and G2/HPs, suggesting that APOL1 risk variants cause podocyte injury partly through enhancing ER stress.
Original language | English |
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Article number | BSR20171713 |
Journal | Bioscience Reports |
Volume | 38 |
Issue number | 4 |
DOIs | |
State | Published - 31 Aug 2018 |
Externally published | Yes |
Bibliographical note
Publisher Copyright:c 2018 The Author(s).
Funding
This work was supported by the National Institutes of Health, Bethesda, MD [grant numbers RO1DK 098074, RO1DK118017 (to P.C.S.)]; the National Institute of General Medical Sciences [grant numbers NIGMS, R01GM063075, 1R41GM123858 (to H.W.)]; and the National Center of Complementary and Alternative Medicine [grant number NCCAM R01AT005076].
Funders | Funder number |
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National Institutes of Health | RO1DK 098074, RO1DK118017 |
National Institute of General Medical Sciences | 1R41GM123858, R01GM063075 |
National Center for Complementary and Alternative Medicine | R01AT005076 |