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.
Highlights
Chronic kidney disease (CKD), which can progress to kidney failure, is influenced by genetics and the environment
We identified genomic loci for urinary protein excretion (UPE) and intermediary serum biochemistries associated with CKD, leading to Septin 8 (Sept8) as a candidate gene linked with renal injury
Consistent with previous findings, 16 out of 245 (6.5%) of the heterogeneous stock (HS) rats exhibited UPE greater than 20 mg/day and are considered to have pathological levels typically noted as proteinuria[22]
Summary
Chronic kidney disease (CKD), which can progress to kidney failure, is influenced by genetics and the environment. 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. Multiple genes have overlapping variant associations with kidney damage in both rat and human including SHROOM3, RAB38, SH2B3, and PLEKHA7 and ARHGEF117–12 These studies show a synergistic nature of both glomerular and tubule genetics in proteinuria and CKD. We identified genomic loci for urinary protein excretion (UPE) and intermediary serum biochemistries associated with CKD, leading to Septin 8 (Sept8) as a candidate gene linked with renal injury. We demonstrate that increased levels of Sept[8] are associated with renal damage in the rat model and use a unique in vitro renal tubule hypoxia model to demonstrate a potential role of SEPTIN8 in cellular structure and organization in response to hypoxia induced stress
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