Genetic susceptibility to diabetic kidney disease is linked to promoter variants of XOR

  • Collins, A. J. et al. Excerpts from the United States Renal Data System 2004 annual data report: atlas of end-stage renal disease in the United States. Am. J. Kidney Dis. 45, A5–A7, S1–280 (2005).

    Article 

    Google Scholar
     

  • Ogurtsova, K. et al. IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res. Clin. Pr. 128, 40–50 (2017).

    Article 
    CAS 

    Google Scholar
     

  • The Diabetes Control and Complications (DCCT) Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int. 47, 1703–1720 (1995).

    Article 

    Google Scholar
     

  • Qi, Z. et al. Characterization of susceptibility of inbred mouse strains to diabetic nephropathy. Diabetes 54, 2628–2637 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Breyer, M. D. et al. Mouse models of diabetic nephropathy. J. Am. Soc. Nephrol. 16, 27–45 (2005).

    Article 
    PubMed 

    Google Scholar
     

  • Susztak, K., Raff, A. C., Schiffer, M. & Bottinger, E. P. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy 2. Diabetes 55, 225–233 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Stieger, N. et al. Impact of high glucose and transforming growth factor-beta on bioenergetic profiles in podocytes. Metab. Clin. Exp. 61, 1073–1086 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zheng, X. et al. Murine glomerular transcriptome links endothelial cell-specific molecule-1 deficiency with susceptibility to diabetic nephropathy. PLoS ONE 12, e0185250 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sol, M. et al. Glomerular endothelial cells as instigators of glomerular sclerotic diseases. Front. Pharmacol. 11, 573557 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kuwabara, A., Satoh, M., Tomita, N., Sasaki, T. & Kashihara, N. Deterioration of glomerular endothelial surface layer induced by oxidative stress is implicated in altered permeability of macromolecules in Zucker fatty rats. Diabetologia 53, 2056–2065 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Qi, H. et al. Glomerular endothelial mitochondrial dysfunction is essential and characteristic of diabetic kidney disease susceptibility. Diabetes 66, 763–778 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Giacco, F. & Brownlee, M. Oxidative stress and diabetic complications. Circ. Res. 107, 1058–1070 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dikalov, S. Cross talk between mitochondria and NADPH oxidases. Free Radic. Biol. Med. 51, 1289–1301 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813–820 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Aliciguzel, Y., Ozen, I., Aslan, M. & Karayalcin, U. Activities of xanthine oxidoreductase and antioxidant enzymes in different tissues of diabetic rats. J. Lab. Clin. Med. 142, 172–177 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Inkster, M. E., Cotter, M. A. & Cameron, N. E. Treatment with the xanthine oxidase inhibitor, allopurinol, improves nerve and vascular function in diabetic rats. Eur. J. Pharmacol. 561, 63–71 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Seaquist, E. R., Goetz, F. C., Rich, S. & Barbosa, J. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N. Engl. J. Med. 320, 1161–1165 (1989).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vardarli, I. et al. Gene for susceptibility to diabetic nephropathy in type 2 diabetes maps to 18q22.3-23. Kidney Int. 62, 2176–2183 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Moczulski, D. K., Rogus, J. J., Antonellis, A., Warram, J. H. & Krolewski, A. S. Major susceptibility locus for nephropathy in type 1 diabetes on chromosome 3q: results of novel discordant sib-pair analysis. Diabetes 47, 1164–1169 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Schelling, J. R. et al. Genome-wide scan for estimated glomerular filtration rate in multi-ethnic diabetic populations: the Family Investigation of Nephropathy and Diabetes (FIND). Diabetes 57, 235–243 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pezzolesi, M. G. et al. Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes. Diabetes 58, 1403–1410 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sheehan, S. et al. Genetic analysis of albuminuria in a cross between C57BL/6J and DBA/2J mice. Am. J. Physiol. Ren. Physiol. 293, F1649–F1656 (2007).

    Article 
    CAS 

    Google Scholar
     

  • Peirce, J. L., Lu, L., Gu, J., Silver, L. M. & Williams, R. W. A new set of BXD recombinant inbred lines from advanced intercross populations in mice. BMC Genet. 5, 7 (2004).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Clee, S. M. et al. Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus. Nat. Genet. 38, 688–693 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Klein, R. F. et al. Regulation of bone mass in mice by the lipoxygenase gene Alox15. Science 303, 229–232 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, X. et al. Joint mouse–human phenome-wide association to test gene function and disease risk. Nat. Commun. 7, 10464 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, X. et al. Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility. Nat. Genet. 37, 365–372 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wu, Y. et al. Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference population. Cell 158, 1415–1430 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Andreux, P. A. et al. Systems genetics of metabolism: the use of the BXD murine reference panel for multiscalar integration of traits. Cell 150, 1287–1299 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Taylor, B. A. in Genetic Variants and Strains of the Laboratory Mouse 2nd edn (eds. Lyon, M. L. & Searle, A. G.) 773–796 (Oxford University Press, 1989).

  • Ohtsubo, T., Rovira, I. I., Starost, M. F., Liu, C. & Finkel, T. Xanthine oxidoreductase is an endogenous regulator of cyclooxygenase-2. Circ. Res. 95, 1118–1124 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Piret, S. E. et al. A mouse model of early-onset renal failure due to a xanthine dehydrogenase nonsense mutation. PLoS ONE 7, e45217 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ohtsubo, T. et al. Xanthine oxidoreductase depletion induces renal interstitial fibrosis through aberrant lipid and purine accumulation in renal tubules. Hypertension 54, 868–876 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kitada, M., Ogura, Y. & Koya, D. Rodent models of diabetic nephropathy: their utility and limitations. Int. J. Nephrol. Renov. 9, 279–290 (2016).

    Article 
    CAS 

    Google Scholar
     

  • Spencer, M. W. et al. Hyperglycemia and hyperlipidemia act synergistically to induce renal disease in LDL receptor-deficient BALB mice. Am. J. Nephrol. 24, 20–31 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ovcharenko, I. et al. Mulan: multiple-sequence local alignment and visualization for studying function and evolution. Genome Res. 15, 184–194 (2005).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Thomas-Chollier, M. et al. Transcription factor binding predictions using TRAP for the analysis of ChIP–seq data and regulatory SNPs. Nat. Protoc. 6, 1860–1869 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rops, A. L. et al. Isolation and characterization of conditionally immortalized mouse glomerular endothelial cell lines. Kidney Int. 66, 2193–2201 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bycroft, C. et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 562, 203–209 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fry, A. et al. Comparison of sociodemographic and health-related characteristics of UK Biobank participants with those of the general population. Am. J. Epidemiol. 186, 1026–1034 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Carroll, R. J., Bastarache, L. & Denny, J. C. R PheWAS: data analysis and plotting tools for phenome-wide association studies in the R environment. Bioinformatics 30, 2375–2376 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sander, J. D. & Joung, J. K. CRISPR–Cas systems for editing, regulating and targeting genomes. Nat. Biotechnol. 32, 347–355 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Seruggia, D. & Montoliu, L. The new CRISPR–Cas system: RNA-guided genome engineering to efficiently produce any desired genetic alteration in animals. Transgenic Res. 23, 707–716 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Leiter, E. H. Multiple low-dose streptozotocin-induced hyperglycemia and insulitis in C57BL mice: influence of inbred background, sex, and thymus. Proc. Natl Acad. Sci. USA 79, 630–634 (1982).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Clotet, S., Riera, M., Pascual, J. & Soler, M. J. RAS and sex differences in diabetic nephropathy. Am. J. Physiol. Renal Physiol. 310, F945–F957 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Oka, H. et al. Lysophosphatidylcholine induces urokinase-type plasminogen activator and its receptor in human macrophages partly through redox-sensitive pathway. Arterioscler. Thromb. Vasc. Biol. 20, 244–250 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rotbain Curovic, V. et al. Soluble urokinase plasminogen activator receptor predicts cardiovascular events, kidney function decline, and mortality in patients with type 1 diabetes. Diabetes Care 42, 1112–1119 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Bouchareb, R., Yu, L., Lassen, E. & Daehn, I. S. Isolation of conditionally immortalized mouse glomerular endothelial cells with fluorescent mitochondria. J. Vis. Exp. doi.org/10.3791/64147 (2022).

  • Susztak, K. et al. Genomic strategies for diabetic nephropathy. J. Am. Soc. Nephrol. 14, S271–S278 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Okamoto, K. et al. An extremely potent inhibitor of xanthine oxidoreductase. Crystal structure of the enzyme-inhibitor complex and mechanism of inhibition. J. Biol. Chem. 278, 1848–1855 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Takano, Y. et al. Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase. Life Sci. 76, 1835–1847 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Malik, U. Z. et al. Febuxostat inhibition of endothelial-bound XO: implications for targeting vascular ROS production. Free Radic. Biol. Med 51, 179–184 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Anderson, S. & Brenner, B. M. The aging kidney: structure, function, mechanisms, and therapeutic implications. J. Am. Geriatr. Soc. 35, 590–593 (1987).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kaplan, C., Pasternack, B., Shah, H. & Gallo, G. Age-related incidence of sclerotic glomeruli in human kidneys. Am. J. Pathol. 80, 227–234 (1975).

    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brandis, A., Bianchi, G., Reale, E., Helmchen, U. & Kuhn, K. Age-dependent glomerulosclerosis and proteinuria occurring in rats of the milan normotensive strain and not in rats of the milan hypertensive strain. Lab. Invest. 55, 234–243 (1986).

    CAS 
    PubMed 

    Google Scholar
     

  • McCrimmon, A. et al. Redox phospholipidomics analysis reveals specific oxidized phospholipids and regions in the diabetic mouse kidney. Redox Biol. 58, 102520 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kadiiska, M. B. et al. Thiazolidinedione treatment decreases oxidative stress in spontaneously hypertensive heart failure rats through attenuation of inducible nitric oxide synthase-mediated lipid radical formation. Diabetes 61, 586–596 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Dijkstra, G. et al. Expression of nitric oxide synthases and formation of nitrotyrosine and reactive oxygen species in inflammatory bowel disease. J. Pathol. 186, 416–421 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ebefors, K. et al. Endothelin receptor-A mediates degradation of the glomerular endothelial surface layer via pathologic crosstalk between activated podocytes and glomerular endothelial cells. Kidney Int. 96, 957–970 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Daehn, I. et al. Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis. J. Clin. Invest. 124, 1608–1621 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kasai, H. & Nishimura, S. Hydroxylation of deoxyguanosine at the C-8 position by ascorbic acid and other reducing agents. Nucleic Acids Res. 12, 2137–2145 (1984).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Leiter, E. H. Differential susceptibility of Balb/C sublines to diabetes induction by multi-dose streptozotocin treatment. Curr. Top. Microbiol. Immunol. 122, 78–85 (1985).

    CAS 
    PubMed 

    Google Scholar
     

  • Schmitt, R. & Melk, A. Molecular mechanisms of renal aging. Kidney Int. 92, 569–579 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Millward, C. A. et al. Mice with a deletion in the gene for CCAAT/enhancer-binding protein β are protected against diet-induced obesity. Diabetes 56, 161–167 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Schroeder-Gloeckler, J. M. et al. CCAAT/enhancer-binding protein deletion reduces adiposity, hepatic steatosis, and diabetes in Leprdb/db mice. J. Biol. Chem. 282, 15717–15729 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lassen, E. & Daehn, I. S. Molecular mechanisms in early diabetic kidney disease: glomerular endothelial cell dysfunction. Int. J. Mol. Sci. 21, 9456 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hong, Q. et al. Hyperuricemia induces endothelial dysfunction via mitochondrial Na+/Ca2+ exchanger-mediated mitochondrial calcium overload. Cell Calcium 51, 402–410 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • d’Ischia, M., Napolitano, A., Manini, P. & Panzella, L. Secondary targets of nitrite-derived reactive nitrogen species: nitrosation/nitration pathways, antioxidant defense mechanisms and toxicological implications. Chem. Res. Toxicol. 24, 2071–2092 (2011).

    Article 
    PubMed 

    Google Scholar
     

  • Tang, C., Livingston, M. J., Liu, Z. & Dong, Z. Autophagy in kidney homeostasis and disease. Nat. Rev. Nephrol. 16, 489–508 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lenoir, O. et al. Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis. Autophagy 11, 1130–1145 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tagawa, A. et al. Impaired podocyte autophagy exacerbates proteinuria in diabetic nephropathy. Diabetes 65, 755–767 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Werner, E. R., Blau, N. & Thony, B. Tetrahydrobiopterin: biochemistry and pathophysiology. Biochem. J. 438, 397–414 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kuzkaya, N., Weissmann, N., Harrison, D. G. & Dikalov, S. Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase. J. Biol. Chem. 278, 22546–22554 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sun, Y. B. et al. Glomerular endothelial cell injury and damage precedes that of podocytes in adriamycin-induced nephropathy. PLoS ONE 8, e55027 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Casalena, G. A. et al. The diabetic microenvironment causes mitochondrial oxidative stress in glomerular endothelial cells and pathological crosstalk with podocytes. Cell Commun. Signal 18, 105 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Khosla, U. M. et al. Hyperuricemia induces endothelial dysfunction. Kidney Int. 67, 1739–1742 (2005).

    Article 
    PubMed 

    Google Scholar
     

  • Jalal, D. I., Maahs, D. M., Hovind, P. & Nakagawa, T. Uric acid as a mediator of diabetic nephropathy. Semin. Nephrol. 31, 459–465 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Washio, K. et al. Xanthine oxidoreductase activity is correlated with insulin resistance and subclinical inflammation in young humans. Metab. Clin. Exp. 70, 51–56 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Miric, D. J. et al. Xanthine oxidase activity in type 2 diabetes mellitus patients with and without diabetic peripheral neuropathy. J. Diabetes Res. 2016, 4370490 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Furuhashi, M. New insights into purine metabolism in metabolic diseases: role of xanthine oxidoreductase activity. Am. J. Physiol. Endocrinol. Metab. 319, E827–E834 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dissanayake, L. V. et al. Lack of xanthine dehydrogenase leads to a remarkable renal decline in a novel hypouricemic rat model. iScience 25, 104887 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, J. et al. Associations of hypertension and its complications with variations in the xanthine dehydrogenase gene. Hypertens. Res. 31, 931–940 (2008).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kudo, M., Sasaki, T., Ishikawa, M., Hirasawa, N. & Hiratsuka, M. Functional characterization of genetic polymorphisms identified in the promoter region of the xanthine oxidase gene. Drug Metab. Pharmacokinet 25, 599–604 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Boban, M. et al. Circulating purine compounds, uric acid, and xanthine oxidase/dehydrogenase relationship in essential hypertension and end stage renal disease. Ren. Fail. 36, 613–618 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Badve, S. V. et al. Effects of allopurinol on the progression of chronic kidney disease. N. Engl. J. Med. 382, 2504–2513 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Doria, A. et al. Serum urate lowering with allopurinol and kidney function in type 1 diabetes. N. Engl. J. Med. 382, 2493–2503 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Goldberg, A. et al. Mini review: reappraisal of uric acid in chronic kidney disease. Am. J. Nephrol. 52, 837–844 (2022).

    Article 

    Google Scholar
     

  • Sanchez-Lozada, L. G. et al. Uric acid-induced endothelial dysfunction is associated with mitochondrial alterations and decreased intracellular ATP concentrations. Nephron Exp. Nephrol. 121, e71–e78 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kim, I. Y., Lee, D. W., Lee, S. B. & Kwak, I. S. The role of uric acid in kidney fibrosis: experimental evidences for the causal relationship. Biomed Res. Int. 2014, 638732 (2014).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Galbusera, C., Orth, P., Fedida, D. & Spector, T. Superoxide radical production by allopurinol and xanthine oxidase. Biochem. Pharmacol. 71, 1747–1752 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Haberland, A., Luther, H. & Schimke, I. Does allopurinol prevent superoxide radical production by xanthine oxidase (XOD)? Agents Actions 32, 96–97 (1991).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Massey, V., Komai, H., Palmer, G. & Elion, G. B. On the mechanism of inactivation of xanthine oxidase by allopurinol and other pyrazolo[3,4-d]pyrimidines. J. Biol. Chem. 245, 2837–2844 (1970).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Horiuchi, H. et al. Allopurinol induces renal toxicity by impairing pyrimidine metabolism in mice. Life Sci. 66, 2051–2070 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lee, H. J. et al. Febuxostat ameliorates diabetic renal injury in a streptozotocin-induced diabetic rat model. Am. J. Nephrol. 40, 56–63 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang, H. et al. One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell 153, 910–918 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gaudet, M., Fara, A.-G., Beritognolo, I. & Sabatti, M. in Single Nucleotide Polymorphisms: Methods and Protocols (ed. Komar, A. A.) 415–424 (Humana Press, 2009).

  • Lee, S. et al. Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. Am. J. Hum. Genet. 91, 224–237 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McLaren, W. et al. The Ensembl Variant Effect Predictor. Genome Biol. 17, 122 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wu, Z. J., Irizarry, R. A., Gentleman, R., Martinez-Murillo, F. & Spencer, F. A model-based background adjustment for oligonucleotide expression arrays. J. Am. Stat. Assoc. 99, 909–917 (2004).

    Article 

    Google Scholar
     

  • Ritchie, M. E. et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ma, L. J. & Fogo, A. B. Model of robust induction of glomerulosclerosis in mice: importance of genetic background. Kidney Int. 64, 350–355 (2003).

    Article 
    PubMed 

    Google Scholar
     

  • Ohno, M., Oka, S. & Nakabeppu, Y. Quantitative analysis of oxidized guanine, 8-oxoguanine, in mitochondrial DNA by immunofluorescence method. Methods Mol. Biol. 554, 199–212 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Feenstra, B., Skovgaard, I. M. & Broman, K. W. Mapping quantitative trait loci by an extension of the Haley–Knott regression method using estimating equations. Genetics 173, 2269–2282 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nakai, K., Kadiiska, M. B., Jiang, J. J., Stadler, K. & Mason, R. P. Free radical production requires both inducible nitric oxide synthase and xanthine oxidase in LPS-treated skin. Proc. Natl Acad. Sci. USA 103, 4616–4621 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stadler, K. et al. Direct evidence of iNOS-mediated in vivo free radical production and protein oxidation in acetone-induced ketosis. Am. J. Physiol. Endocrinol. Metab. 295, E456–E462 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Read more here: Source link