APOL1 risk variants cause podocytes injury through enhancing endoplasmic reticulum stress

Hongxiu Wen, Vinod Kumar, Xiqian Lan, Seyedeh Shadafarin Marashi Shoshtari, Judith M. Eng, Xiaogang Zhou, Fang Wang, Haichao Wang, Karl Skorecki, Guolan Xing, Guisheng Wu, Huairong Luo, Ashwani Malhotra, Pravin C. Singhal

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44 Scopus citations

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 languageEnglish
Article numberBSR20171713
JournalBioscience Reports
Volume38
Issue number4
DOIs
StatePublished - 31 Aug 2018
Externally publishedYes

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].

FundersFunder number
National Institutes of HealthRO1DK 098074, RO1DK118017
National Institute of General Medical Sciences1R41GM123858, R01GM063075
National Center for Complementary and Alternative MedicineR01AT005076

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