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A Personalized Model of COQ2 Nephropathy Rescued by the Wild-Type COQ2 Allele Or Dietary Coenzyme Q10 Supplementation

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A Personalized Model of COQ2 Nephropathy Rescued by the Wild-Type COQ2 Allele Or Dietary Coenzyme Q10 Supplementation BASIC RESEARCH www.jasn.org A Personalized Model of COQ2 Nephropathy Rescued by the Wild-Type COQ2 Allele or Dietary Coenzyme Q10 Supplementation † ‡ Jun-yi Zhu,* Yulong Fu,* Adam Richman,* Zhanzheng Zhao, Patricio E. Ray, § and Zhe Han*§ Centers for *Cancer and Immunology Research and ‡Genetic Medicine Research, Children’s National Health System, Washington, DC; †Department of Nephrology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; and §Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC ABSTRACT Clinical studies have identified patients with nephrotic syndrome caused by mutations in genes involved in the biosynthesis of coenzyme Q10 (CoQ10), a lipid component of the mitochondrial electron transport chain and an important antioxidant. However, the cellular mechanisms through which these mutations induce podocyte injury remain obscure. Here, we exploited the striking similarities between Drosophila nephrocytes and human podocytes to develop a Drosophila model of these renal diseases, and performed a systematic in vivo analysis assessing the role of CoQ10 pathway genes in renal function. Nephrocyte-specific silencing of Coq2, Coq6,andCoq8, which are genes involved in the CoQ10 pathway that have been associated with genetic nephrotic syndrome in humans, induced dramatic adverse changes in these cells. In particular, silencing of Coq2 led to an abnormal localization of slit diaphragms, collapse of lacunar channels, and more dysmorphic mitochondria. In addition, Coq2-deficient nephrocytes showed elevated levels of autophagy and mitophagy, increased levels of reactive oxygen species, and increased sensitivity to oxidative stress. Dietary supplementation with CoQ10 at least partially rescued these defects. Furthermore, expressing the wild-type human COQ2 gene specifically in nephrocytes rescued the de- fective protein uptake, but expressing the mutant allele derived from a patient with COQ2 nephropathy did not. We conclude that transgenic Drosophila lines carrying mutations in the CoQ10 pathway genes are clinically relevant models with which to explore the pathogenesis of podocyte injury and could serve as a new platform to test novel therapeutic approaches. J Am Soc Nephrol 28: 2607–2617, 2017. doi: https://doi.org/10.1681/ASN.2016060626 Steroid-resistant nephrotic syndrome (SRNS) is a The Drosophila pericardial nephrocyte (hereaf- major cause of end stage renal disease (ESRD).1–5 ter, nephrocyte) bears striking structural and func- The identification of single gene mutations associ- tional similarities to the mammalian podocyte.10–12 ated with SRNS have yielded insights into patho- genic mechanisms, and evidence from multiple Received June 8, 2016. Accepted March 9, 2017. studies points to the podocyte as an important tar- get of cellular injury.4,6–9 Increased understanding J.-y.Z. and Y.F. contributed equally to this work. of molecular and cellular processes that are affected Published online ahead of print. Publication date available at by mutations, and the development of new thera- www.jasn.org. peutic treatment approaches, will be greatly aided Correspondence: Dr. Zhe Han, Children’s Research Institute, by development of an animal model system that Children’s National Health System, 111 Michigan Avenue NW, permits in vivo experimental studies relevant for Washington, DC 20010. Email: [email protected] elucidating podocyte cell function and cytotoxicity. Copyright © 2017 by the American Society of Nephrology J Am Soc Nephrol 28: 2607–2617, 2017 ISSN : 1046-6673/2809-2607 2607 BASIC RESEARCH www.jasn.org Table 1. Genes involved in CoQ biosynthesis and associated with clinical renal pathology Representative Human Gene Name Protein Function Drosophila Ortholog Conservation Score Nephropathy PDSS1 (COQ1 subunit 1) Catalytic subunit of COQ1, Qless 9 None identified synthesis of CoQ polyisoprene tail PDSS2 (COQ1 subunit 2) Regulatory subunit of COQ1 Pdss2 (CG10585) 10 NS COQ2 Transferase, links Coq2 (CG9613) 10 FSGS parahydroxybenzoate redox-active head precursor to polyisoprene tail COQ3 Methylase, modification of Coq3 (CG9249) 10 None identified CoQ redox-active head COQ4 Unknown function Coq4 (CG32174) 10 None identified (regulatory?) COQ5 Methylase, modification of Coq5 (CG2453) 9 None identified CoQ redox-active head COQ6 Hydroxylase, modification of Coq6 (CG7277) 10 SRNS CoQ redox-active head COQ7 Hydroxylase, modification of Coq7 (CG14437) 8 None identified CoQ redox-active head COQ8 (ADCK4) Kinase (regulatory?) Coq8/Adck4 (CG32649) 9 SRNS COQ9 Unknown function (regulatory?) Coq9 (CG30493) 10 Renal tubulopathy Human COQ genes and Drosophila orthologs are shown, with degree of homology (conservation score: 1–10 [lowest to highest] scale).34 Representative mani- festations of kidney disease are indicated for mutation of PDSS2,16 COQ2,17 COQ6,9 COQ8,4 and COQ9.35 Combining this feature with the extensive genetic resources RESULTS available in Drosophila for conditionally manipulating gene expression in specific cells and tissues at distinct stages, we Silencing CoQ10 Biosynthesis Pathway Genes in have developed the fly as a model system to investigate Nephrocytes genetic, molecular, and cellular targets of cell injury in The CoQ10 synthesis pathway genes are highly conserved from nephrocytes that are relevant to podocytes, thereby con- Drosophila to humans. In humans, the genes include PDSS1 tributing to understanding of renal cell injury and kidney (COQ1 subunit 1), PDSS2 (COQ1 subunit 2), COQ2, COQ3, disease processes.4,5,13–15 COQ4, COQ5, COQ6, COQ7, COQ8,andCOQ9.Theirfunc- Coenzyme Q10 (CoQ10)deficiencies have been linked to tions are listed in Table 1. In Drosophila, the homologs of severe renal pathologies including SRNS, collapsing glo- PDSS1 and COQ2 are named Qless and Coq2,respectively. 4,6,9,16,17 merulopathy, and tubular interstitial diseases. Here, we have named the remaining Drosophila CoQ10 syn- Among genes encoding enzymes involved in the biosynthe- thesis pathway genes Pdss2, Coq3, Coq4, Coq5, Coq6, Coq7, sis of CoQ10, mutations in PDSS2, COQ2, COQ6, COQ8, Coq8,andCoq9, corresponding to their human homologs and COQ9 have been linked to renal pathologies.4,6,9,16 (Table 1). The human genes that have been associated with CoQ10 plays an essential role in the mitochondrial respira- the development of nephrotic syndrome (NS), focal glomer- tory chain and protects against damage from reactive oxy- ulosclerosis (FSGS), SRNS, and renal tubulopathy are indi- 6,18,19 gen species (ROS). The precise mechanism of CoQ10 cated in Table 1. We generated Drosophila transgenic lines in deficiency induced cellular pathology is not defined, but which specific Coq gene expression was silenced in nephro- occurs in the context of abnormal mitochondrial function and cytes. This strategy used the UAS-Gal4 system21 in which flies increased ROS formation.18 Patients carrying mutations result- carried a Dot-Gal4 driver construct whereby the Dot gene en- 22 fi 5,13–15 ing in primary CoQ10 deficiency present with very heterogeneous hancer directed nephrocyte-speci c expression of the symptoms.19 It remains unclear why some patients manifest yeast Gal4 transcription factor, which in turn promoted ex- with severe renal disease. CoQ10 deficiency is unique among pression of a UAS-Coq-RNAi transgene that silenced the en- mitochondrial disorders in that early supplementation with dogenous Coq target gene. 9,20 CoQ10 can prevent the onset of disease. Here, we utilized Drosophila as an in vivo model system to Coq Gene Silencing Affected Nephrocyte Cell Function investigate the phenotypes associated with CoQ10 deficiency The principal functions of the nephrocyte are first, to filter induced by the systematic silencing of all of the fly Coq genes hemolymph, and second, to take up filtered low molecular specifically in nephrocytes. Our findings validate the clinical weight proteins and toxins for recycling and sequestration, relevance of our experimental model system to study the path- respectively.11,12 We took advantage of the second role to de- ogenesis of CoQ10-related human renal diseases. velop in vivo quantitative assays to measure the effects of gene 2608 Journal of the American Society of Nephrology J Am Soc Nephrol 28: 2607–2617, 2017 www.jasn.org BASIC RESEARCH silencing on nephrocyte uptake functions. We examined the ability of nephrocytes ex- pressing Coq gene silencing RNAi trans- genes to take up a fluorescent hemolymph marker protein. In this assay, flies carried a MHC-ANF-RFP transgene, in which a myosin heavy chain (MHC) promoter drove expression of an atrial natriuretic peptide- red fluorescent protein (ANF-RFP) fusion protein. Muscle cells secreted ANF-RFP into the fly hemolymph from which it was filtered and endocytosed by nephro- cytes, and intracellular fluorescence was detected and quantitated.14 To confirm nephrocyte cell identity, flies also carried a green fluorescent protein (GFP) transgene ex- pressed under the control of the Drosophila Hand gene promoter (Hand-GFP).23 MHC-ANF-RFP and Hand-GFP trans- genes were combined in flies carrying Dot-Gal4 driver22 and UAS-Coq-RNAi constructs silencing the endogenous Coq Figure 1. Hemolymph protein marker ANF-RFP and AgNO levels in nephrocytes target genes in nephrocytes. 3 expressing Coq-RNAi transgenes. (A) Fluorescence micrographs showing nephrocytes We systematically examined the effects of adult flies 1-day postemergence. ANF-RFP fluorescence (red) is shown in the left on ANF-RFP fusion protein uptake of panels. Right
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