APOL1 renal risk variants exacerbate podocyte injury by increasing inflammatory stress

Hidefumi Wakashin,Parnaz Daneshpajouhnejad,Jurgen Heymann,Avi Rosenberg,Jeffrey B Kopp,Myung Kyun Shin,Maarten Hoek,Hila Roshanravan

doi:10.1186/s12882-020-01995-3

Abstract

BackgroundApolipoprotein 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.ObjectivesWe focus on the mechanism how APOL1 variant proteins enhance podocyte injury in the stressed kidney.MethodsFirst, 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.ResultsWe 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-IL-1β 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.ConclusionsThese 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.

Highlights

African Americans have increased rates of chronic kidney disease, and a major cause of this health disparity are Apolipoprotein L1 (APOL1) genetic variants, present exclusively in individuals of African descent [1]
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
As most APOL1 nephropathies are either podocyte diseases or glomerular and vascular diseases, it appears that APOL1 risk variant expression in podocytes and possibly renal vascular cells contributes to kidney disease

Summary

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 gene variants are strongly associated with risk for focal segmental glomerulosclerosis (FSGS), HIVassociated nephropathy (HIVAN), and hypertensionattributed kidney disease (arterionephrosclerosis) [1]. APOL1 risk allele status in deceased donor kidneys affects transplant kidney survival [3], while the APOL1 risk allele status of the recipient does not affect transplant kidney survival [4]. These data suggest that intra-renal APOL1 expression, rather than circulating APOL1, is associated with kidney disease. As most APOL1 nephropathies are either podocyte diseases (focal segmental glomerulosclerosis, HIV-associated nephropathy) or glomerular and vascular diseases (arterionephrosclerosis), it appears that APOL1 risk variant expression in podocytes and possibly renal vascular cells contributes to kidney disease. 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

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Conclusion