APOL1 renal risk variants exacerbate podocyte injury by increasing inflammatory stress
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RESEARCH ARTICLE
Open Access
APOL1 renal risk variants exacerbate podocyte injury by increasing inflammatory stress Hidefumi Wakashin1, Jurgen Heymann1, Hila Roshanravan1, Parnaz Daneshpajouhnejad2, Avi Rosenberg2, Myung Kyun Shin3, Maarten Hoek4 and Jeffrey B. Kopp1*
Abstract Background: Apolipoprotein L1, APOL1, is a trypanosome lytic factor present in human and certain other primates. APOL1 gene variants, present in individuals of recent sub-Saharan African descent, increase risk for glomerular disease and associate with the disease progression, but the molecular mechanisms have not been defined. Objectives: We focus on the mechanism how APOL1 variant proteins enhance podocyte injury in the stressed kidney. Methods: First, we investigated the expression of APOL1 protein isoform and the localization of APOL1 protein in the kidney. Next, we examined the role of APOL1 in the podocyte stress and the inflammatory signaling in the kidney after hemi-nephrectomy. Results: We identified a novel RNA variant that lacks a secretory pathway signal sequence and we found that the predicted APOL1-B3 protein isoform was expressed in human podocytes in vivo and by BAC-APOL1 transgenic mice. APOL1-B3-G2 transgenic mice, carrying a renal risk variant, manifested podocyte injury and increased pro-IL1β mRNA in isolated glomeruli and increased IL-1β production in the remnant kidney after uninephrectomy. APOL1-B3 interacted with NLRP12, a key regulator of Toll-like receptor signaling. Conclusions: These results suggest a possible mechanism for podocyte injury by which one of the APOL1 protein isoforms, APOL1-B3 and its renal risk variants, enhances inflammatory signaling. Keywords: APOL1, Protein isoform, Interleukin-1 beta, NLRP12, Podocytes, Kidney, Chronic kidney disease, Inflammatory stress
Introduction African Americans have increased rates of chronic kidney disease, and a major cause of this health disparity are APOL1 genetic variants, present exclusively in individuals of African descent [1]. APOL1 kill Trypanosoma brucei, likely via formation of pores that serve as ion channels [2]. T. b. rhodesiense possesses a protein, serum * Correspondence: [email protected] 1 Kidney Disease Section, NIDDK, NIH, KDB, 10 Center Dr, 3N116, Bethesda, MD 20892-1268, USA Full list of author information is available at the end of the article
resistance antigen (SRA), which binds APOL1 and prevents pore formation. The human APOL1 coding variants, termed G1 and G2, in contrast to the more widespread G0 isoform, elude binding by SRA and kill T. b. rhodesiense. The G1 variant has two nonsynonymous coding variants (S342G) and (I384M) and in the G2 variant, N388 and Y389 are deleted. APOL1 gene variants are strongly associated with risk for focal segmental glomerulosclerosis (FSGS), HIVassociated nephropathy (HIVAN), and hypertensionattributed kidney disease (arterionephrosclerosis) [1].
© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, d
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