Sept8/SEPTIN8 involvement in cellular structure and kidney damage is identified by genetic mapping and a novel human tubule hypoxic model

Abstract Chronic kidney disease (CKD), which can ultimately progress to kidney failure, is influenced by genetics and the environment. Genes identified in human genome wide association studies (GWAS) explain only a small proportion of the heritable variation and lack functional validation, indicatin...

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Autores principales:	Gregory R. Keele, Jeremy W. Prokop, Hong He, Katie Holl, John Littrell, Aaron W. Deal, Yunjung Kim, Patrick B. Kyle, Esinam Attipoe, Ashley C. Johnson, Katie L. Uhl, Olivia L. Sirpilla, Seyedehameneh Jahanbakhsh, Melanie Robinson, Shawn Levy, William Valdar, Michael R. Garrett, Leah C. Solberg Woods
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6d41003b7a614d5f9d1574c3f69d76e1
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spelling	oai:doaj.org-article:6d41003b7a614d5f9d1574c3f69d76e12021-12-02T11:50:30ZSept8/SEPTIN8 involvement in cellular structure and kidney damage is identified by genetic mapping and a novel human tubule hypoxic model10.1038/s41598-021-81550-82045-2322https://doaj.org/article/6d41003b7a614d5f9d1574c3f69d76e12021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81550-8https://doaj.org/toc/2045-2322Abstract Chronic kidney disease (CKD), which can ultimately progress to kidney failure, is influenced by genetics and the environment. Genes identified in human genome wide association studies (GWAS) explain only a small proportion of the heritable variation and lack functional validation, indicating the need for additional model systems. Outbred heterogeneous stock (HS) rats have been used for genetic fine-mapping of complex traits, but have not previously been used for CKD traits. We performed GWAS for urinary protein excretion (UPE) and CKD related serum biochemistries in 245 male HS rats. Quantitative trait loci (QTL) were identified using a linear mixed effect model that tested for association with imputed genotypes. Candidate genes were identified using bioinformatics tools and targeted RNAseq followed by testing in a novel in vitro model of human tubule, hypoxia-induced damage. We identified two QTL for UPE and five for serum biochemistries. Protein modeling identified a missense variant within Septin 8 (Sept8) as a candidate for UPE. Sept8/SEPTIN8 expression increased in HS rats with elevated UPE and tubulointerstitial injury and in the in vitro hypoxia model. SEPTIN8 is detected within proximal tubule cells in human kidney samples and localizes with acetyl-alpha tubulin in the culture system. After hypoxia, SEPTIN8 staining becomes diffuse and appears to relocalize with actin. These data suggest a role of SEPTIN8 in cellular organization and structure in response to environmental stress. This study demonstrates that integration of a rat genetic model with an environmentally induced tubule damage system identifies Sept8/SEPTIN8 and informs novel aspects of the complex gene by environmental interactions contributing to CKD risk.Gregory R. KeeleJeremy W. ProkopHong HeKatie HollJohn LittrellAaron W. DealYunjung KimPatrick B. KyleEsinam AttipoeAshley C. JohnsonKatie L. UhlOlivia L. SirpillaSeyedehameneh JahanbakhshMelanie RobinsonShawn LevyWilliam ValdarMichael R. GarrettLeah C. Solberg WoodsNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gregory R. Keele Jeremy W. Prokop Hong He Katie Holl John Littrell Aaron W. Deal Yunjung Kim Patrick B. Kyle Esinam Attipoe Ashley C. Johnson Katie L. Uhl Olivia L. Sirpilla Seyedehameneh Jahanbakhsh Melanie Robinson Shawn Levy William Valdar Michael R. Garrett Leah C. Solberg Woods Sept8/SEPTIN8 involvement in cellular structure and kidney damage is identified by genetic mapping and a novel human tubule hypoxic model
description	Abstract Chronic kidney disease (CKD), which can ultimately progress to kidney failure, is influenced by genetics and the environment. Genes identified in human genome wide association studies (GWAS) explain only a small proportion of the heritable variation and lack functional validation, indicating the need for additional model systems. Outbred heterogeneous stock (HS) rats have been used for genetic fine-mapping of complex traits, but have not previously been used for CKD traits. We performed GWAS for urinary protein excretion (UPE) and CKD related serum biochemistries in 245 male HS rats. Quantitative trait loci (QTL) were identified using a linear mixed effect model that tested for association with imputed genotypes. Candidate genes were identified using bioinformatics tools and targeted RNAseq followed by testing in a novel in vitro model of human tubule, hypoxia-induced damage. We identified two QTL for UPE and five for serum biochemistries. Protein modeling identified a missense variant within Septin 8 (Sept8) as a candidate for UPE. Sept8/SEPTIN8 expression increased in HS rats with elevated UPE and tubulointerstitial injury and in the in vitro hypoxia model. SEPTIN8 is detected within proximal tubule cells in human kidney samples and localizes with acetyl-alpha tubulin in the culture system. After hypoxia, SEPTIN8 staining becomes diffuse and appears to relocalize with actin. These data suggest a role of SEPTIN8 in cellular organization and structure in response to environmental stress. This study demonstrates that integration of a rat genetic model with an environmentally induced tubule damage system identifies Sept8/SEPTIN8 and informs novel aspects of the complex gene by environmental interactions contributing to CKD risk.
format	article
author	Gregory R. Keele Jeremy W. Prokop Hong He Katie Holl John Littrell Aaron W. Deal Yunjung Kim Patrick B. Kyle Esinam Attipoe Ashley C. Johnson Katie L. Uhl Olivia L. Sirpilla Seyedehameneh Jahanbakhsh Melanie Robinson Shawn Levy William Valdar Michael R. Garrett Leah C. Solberg Woods
author_facet	Gregory R. Keele Jeremy W. Prokop Hong He Katie Holl John Littrell Aaron W. Deal Yunjung Kim Patrick B. Kyle Esinam Attipoe Ashley C. Johnson Katie L. Uhl Olivia L. Sirpilla Seyedehameneh Jahanbakhsh Melanie Robinson Shawn Levy William Valdar Michael R. Garrett Leah C. Solberg Woods
author_sort	Gregory R. Keele
title	Sept8/SEPTIN8 involvement in cellular structure and kidney damage is identified by genetic mapping and a novel human tubule hypoxic model
title_short	Sept8/SEPTIN8 involvement in cellular structure and kidney damage is identified by genetic mapping and a novel human tubule hypoxic model
title_full	Sept8/SEPTIN8 involvement in cellular structure and kidney damage is identified by genetic mapping and a novel human tubule hypoxic model
title_fullStr	Sept8/SEPTIN8 involvement in cellular structure and kidney damage is identified by genetic mapping and a novel human tubule hypoxic model
title_full_unstemmed	Sept8/SEPTIN8 involvement in cellular structure and kidney damage is identified by genetic mapping and a novel human tubule hypoxic model
title_sort	sept8/septin8 involvement in cellular structure and kidney damage is identified by genetic mapping and a novel human tubule hypoxic model
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/6d41003b7a614d5f9d1574c3f69d76e1
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Sept8/SEPTIN8 involvement in cellular structure and kidney damage is identified by genetic mapping and a novel human tubule hypoxic model

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