Sweet Debate: Fructose versus Glucose in Diabetic Kidney Disease

EDITORIALS

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are mutated in individuals with NPHP, localize to nuclear foci and mediate DNA damage response signaling.8,9 In summary, the findings of Cong et al. are the first to demonstrate that mutation of a ciliary gene causes glomerular disease.3 The molecular mechanism by which TTC21B affects the cytoskeleton remains to be investigated. Additionally, whether TTC21B extraciliary function extends to other underlying mechanisms of podocyte damage, such as calcium signaling and lysosomal function, are other areas for future exploration. The first reports linking defective primary cilia to renal cystogenesis caused a resurgence of ciliary research. Similarly, the novel findings of Cong et al. are likely to spur new investigations into the extraciliary role of IFT proteins in renal cell biology and pathobiology. ACKNOWLEDGMENTS The author thanks Drs. D. Abrahamson and I. Saadi (University of Kansas Medical Center) for their very helpful comments. P.V.T. is supported by an American Society of Nephrology Gottschalk Research Scholar Award and a National Institutes of Health Center of Biomedical Research Excellence grant (P20-GM104936-06).

DISCLOSURES None.

See related article, “A Homozygous Missense Mutation in the Ciliary Gene TTC21B Causes Familial FSGS,” on pages 2435–2443.

Sweet Debate: Fructose versus Glucose in Diabetic Kidney Disease Pazit Beckerman and Katalin Susztak

REFERENCES 1. Tran PV, Haycraft CJ, Besschetnova TY, Turbe-Doan A, Stottmann RW, Herron BJ, Chesebro AL, Qiu H, Scherz PJ, Shah JV, Yoder BK, Beier DR: THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia. Nat Genet 40: 403–410, 2008 2. Davis EE, Zhang Q, Liu Q, Diplas BH, Davey LM, Hartley J, Stoetzel C, Szymanska K, Ramaswami G, Logan CV, Muzny DM, Young AC, Wheeler DA, Cruz P, Morgan M, Lewis LR, Cherukuri P, Maskeri B, Hansen NF, Mullikin JC, Blakesley RW, Bouffard GG, Gyapay G, Rieger S, Tönshoff B, Kern I, Soliman NA, Neuhaus TJ, Swoboda KJ, Kayserili H, Gallagher TE, Lewis RA, Bergmann C, Otto EA, Saunier S, Scambler PJ, Beales PL, Gleeson JG, Maher ER, Attié-Bitach T, Dollfus H, Johnson CA, Green ED, Gibbs RA, Hildebrandt F, Pierce EA, Katsanis N; NISC Comparative Sequencing Program: TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. Nat Genet 43: 189–196, 2011 3. Cong EHB, Bizet AA, Boyer O, Woerner S, Gribouval O, Filhol E, Arrondel C, Thomas S, Silbermann F, Canaud G, Hachicha J, Dhia NB, Peraldi MN, Harzallah K, Iftene D, Daniel L, Willems M, Noel LH, BoleFeysot C, Nitcschké P, Gubler MC, Mollet G, Saunier S, Antignac C: A homozygous missense mutation in the ciliary gene TTC21B causes familial FSGS. J Am Soc Nephrol 25: 2435–2443, 2014 4. Akchurin O, Reidy KJ: Genetic causes of proteinuria and nephrotic syndrome: Impact on podocyte pathobiology [published online ahead of print March 2, 2012]. Pediatr Nephrol doi: 10.1007/s00467-014-2753-3 5. Ichimura K, Kurihara H, Sakai T: Primary cilia disappear in rat podocytes during glomerular development. Cell Tissue Res 341: 197–209, 2010 6. Delaval B, Bright A, Lawson ND, Doxsey S: The cilia protein IFT88 is required for spindle orientation in mitosis. Nat Cell Biol 13: 461–468, 2011 7. Follit JA, San Agustin JT, Xu F, Jonassen JA, Samtani R, Lo CW, Pazour GJ: The Golgin GMAP210/TRIP11 anchors IFT20 to the Golgi complex. PLoS Genet 4: e1000315, 2008 8. Choi HJ, Lin JR, Vannier JB, Slaats GG, Kile AC, Paulsen RD, Manning DK, Beier DR, Giles RH, Boulton SJ, Cimprich KA: NEK8 links the

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ATR-regulated replication stress response and S phase CDK activity to renal ciliopathies. Mol Cell 51: 423–439, 2013 9. Chaki M, Airik R, Ghosh AK, Giles RH, Chen R, Slaats GG, Wang H, Hurd TW, Zhou W, Cluckey A, Gee HY, Ramaswami G, Hong CJ, Hamilton BA, Cervenka I, Ganji RS, Bryja V, Arts HH, van Reeuwijk J, Oud MM, Letteboer SJ, Roepman R, Husson H, Ibraghimov-Beskrovnaya O, Yasunaga T, Walz G, Eley L, Sayer JA, Schermer B, Liebau MC, Benzing T, Le Corre S, Drummond I, Janssen S, Allen SJ, Natarajan S, O’Toole JF, Attanasio M, Saunier S, Antignac C, Koenekoop RK, Ren H, Lopez I, Nayir A, Stoetzel C, Dollfus H, Massoudi R, Gleeson JG, Andreoli SP, Doherty DG, Lindstrad A, Golzio C, Katsanis N, Pape L, Abboud EB, Al-Rajhi AA, Lewis RA, Omran H, Lee EY, Wang S, Sekiguchi JM, Saunders R, Johnson CA, Garner E, Vanselow K, Andersen JS, Shlomai J, Nurnberg G, Nurnberg P, Levy S, Smogorzewska A, Otto EA, Hildebrandt F: Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell 150: 533–548, 2012

Journal of the American Society of Nephrology

Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania J Am Soc Nephrol 25: 2386–2388, 2014. doi: 10.1681/ASN.2014050433

The prevalence of diabetes continues to increase worldwide.1 Renal disease shows the strongest correlation with excess mortality in diabetes, yet the mechanisms of diabetic kidney disease (DKD) remain poorly understood. It has been repeatedly demonstrated that hyperglycemia plays a crucial role in DKD initiation, both in patients and in animal models. Cells that are unable to downregulate their glucose transporters in response to hyperglycemia will experience increased intracellular glucose flux.2 Intracellular glucose is eventually metabolized to pyruvate by a series of enzymatic reactions called glycolysis. Intracellular glucose is first rapidly converted via an energy-dependent mechanism into fructose 6-phosphate and then by the phosphofructokinase to fructose 1,6-phosphate. Phosphofructokinase is a rate-limiting enzyme in glycolysis. Fructose 6-phosphate can also be diverted into the hexosamine pathway to become glucosamine, an important potential mediator of diabetic complications. Published online ahead of print. Publication date available at www.jasn.org. Correspondence: Dr. Katalin Susztak, Renal Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, 415 Curie Boulevard, 415 Clinical Research Building, Philadelphia, PA 19104. Email: [email protected] Copyright © 2014 by the American Society of Nephrology

J Am Soc Nephrol 25: 2385–2392, 2014

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Increased fructose consumption has been suggested to play a role in obesity, hypertension, and metabolic syndrome development. There is a correlation between the use of high fructose corn syrup and the increase in obesity rates in the United States.3 Dietary fructose mostly enters the cells via glucose transporter-5 and is metabolized, primarily in the liver, by phosphorylation on the 1-position by the hexokinase also known as fructokinase or ketohexokinase (Khk) enzyme, a process that bypasses the ratelimiting phosphofructokinase step in glycolysis. There are slight differences in glucose versus fructose metabolism because fructose results in trioses that lack phosphate thus need to be phosphorylated for mitochondrial oxidation. Hepatic metabolism of fructose favors lipogenesis because fructose metabolites contribute to triglyceride backbone structure. Furthermore, the ADP formed from ATP after phosphorylation of fructose on the 1-position can be further metabolized to uric acid,4 which utilizes nitric oxide, a key modulator of vascular function. Indeed, an association between fructose intake, uric acid, and triglyceride levels has been observed.3 In addition to dietary fructose, intracellular glucose can be converted into fructose by the aldose reductase enzyme in the polyol pathway.5 Aldose reductase and the polyol pathways play an important role in the development of diabetic complications. Increased accumulation of intracellular reactive oxygen species is considered the final common mechanism that mediates hyperglycemia-induced intracellular biochemical changes and development of diabetic complications. Increased reactive oxygen species generation can cause increased cell stress and apoptosis and is also shown to turn on the pleiotropic transcription factor NF-kB.6,7 NF-kB is an important regulator of the immune system and its activation has been reported in patient samples and animal models with DKD.8 Increased NF-kB activation is associated with increased expression of proinflammatory cytokines, including monocyte chemoattractant protein-1/chemokine (C-C motif) ligand 29 and TNF-a.10 TNF-a levels positively correlate with and can predict DKD development in patients with type 1 or type 2 diabetes. In addition, genetic ablation or inhibition of monocyte chemoattractant protein-1 significantly ameliorates DKD development in animal models.11 Although DKD was traditionally grouped under nonimmune-mediated kidney diseases, recent reports suggest that inflammation and cytokines play an important role in DKD development.12 In this issue of JASN, Lanaspa et al.13 add yet another piece to the complex picture of the metabolic basis of DKD. Lanaspa et al. examined the role of endogenous fructose in the pathogenesis of DKD in vivo, by using a fructokinase-deficient mouse model (Khk2/2). The authors demonstrate that endogenous fructose, produced from glucose in diabetes through the activation of the polyol pathway in the proximal tubule, is involved in development of tubulointerstitial inflammation and renal injury. Wild-type diabetic (streptozotocin-induced) mice developed metabolic characteristics of diabetes and histologic features of diabetic nephropathy. Although Khk2/2 knockout mice developed a similar degree of hyperglycemia, they were relatively protected from renal injury, as manifested by both laboratory and histologic parameters. J Am Soc Nephrol 25: 2385–2392, 2014

EDITORIALS

Lanaspa et al.13 speculated that a blunted inflammatory response, including a lower expression of inflammatory cytokines and reduced abundance of macrophages in the renal cortex, is responsible for the protective phenotype. The diminished inflammatory response, including decreased NF-kB activation, was also demonstrated in vitro in HK-2 proximal tubule cells, in which KHK expression was silenced. The pathogenic activation of the proinflammatory system in diabetic proximal tubules was induced through the excessive activation of the polyol pathway and resulting oxidative stress. The authors found higher expression of aldose reductase, as well as increased levels of fructose and sorbitol in diabetic mice consistent with the activation of the polyol pathway. In addition, uric acid and superoxide levels were increased, whereas ATP levels were lower in diabetic mice. Some of these features were blunted in the Khk2/2 knockout animals. Interestingly, although most of these changes took place in proximal tubule cells, glomerular injury was also reduced in diabetic Khk2/2 knockout mice. The importance of these findings and the polyol-fructose pathway in human diabetic nephropathy is still to be determined, because data in humans supporting a causal link between fructose metabolism and DKD are lacking. Whether the kidney indeed uses glucose as its primary energy source is another important issue that is yet to be resolved. Different lines of evidence suggest that fatty acids are a major source of ATP in renal cells.14,15 Increased reliance of glucose oxidation is an important characteristic of clear cell renal cancer. Therefore, the significance of polyol pathway induction and fructose metabolism in DKD in humans, especially as a potential therapeutic target, is still elusive. Further studies are needed to examine renal epithelial cell metabolism at baseline and in the diabetic condition. ACKNOWLEDGMENTS Work in the Susztak laboratory is supported by the National Institutes of Health and the American Diabetes Association.

DISCLOSURES The Susztak laboratory receives research support from Boehringer Ingelheim.

REFERENCES 1. US Renal Data System: USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, Bethesda, MD, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2013 2. Schiffer M, Susztak K, Ranalletta M, Raff AC, Böttinger EP, Charron MJ: Localization of the GLUT8 glucose transporter in murine kidney and regulation in vivo in nondiabetic and diabetic conditions. Am J Physiol Renal Physiol 289: F186–F193, 2005 3. Johnson RJ, Nakagawa T, Sanchez-Lozada LG, Shafiu M, Sundaram S, Le M, Ishimoto T, Sautin YY, Lanaspa MA: Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes 62: 3307–3315, 2013 4. Dunlop M: Aldose reductase and the role of the polyol pathway in diabetic nephropathy. Kidney Int Suppl 58: S3–S12, 2000

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EDITORIALS

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5. Cirillo P, Gersch MS, Mu W, Scherer PM, Kim KM, Gesualdo L, Henderson GN, Johnson RJ, Sautin YY: Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells. J Am Soc Nephrol 20: 545–553, 2009 6. Susztak K, Raff AC, Schiffer M, Böttinger EP: Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes 55: 225 –233, 2006 7. Giacco F, Brownlee M: Oxidative stress and diabetic complications. Circ Res 107: 1058–1070, 2010 8. Woroniecka KI, Park AS, Mohtat D, Thomas DB, Pullman JM, Susztak K: Transcriptome analysis of human diabetic kidney disease. Diabetes 60: 2354–2369, 2011 9. Ha H, Yu MR, Choi YJ, Kitamura M, Lee HB: Role of high glucose-induced nuclear factor-kappaB activation in monocyte chemoattractant protein-1 expression by mesangial cells. J Am Soc Nephrol 13: 894–902, 2002 10. Niewczas MA, Ficociello LH, Johnson AC, Walker W, Rosolowsky ET, Roshan B, Warram JH, Krolewski AS: Serum concentrations of markers of TNFalpha and Fas-mediated pathways and renal function in nonproteinuric patients with type 1 diabetes. Clin J Am Soc Nephrol 4: 62–70, 2009 11. Ninichuk V, Clauss S, Kulkarni O, Schmid H, Segerer S, Radomska E, Eulberg D, Buchner K, Selve N, Klussmann S, Anders HJ: Late onset of Ccl2 blockade with the Spiegelmer mNOX-E36-39PEG prevents glomerulosclerosis and improves glomerular filtration rate in db/db mice. Am J Pathol 172: 628–637, 2008 12. Navarro-González JF, Mora-Fernández C, Muros de Fuentes M, GarcíaPérez J: Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol 7: 327–340, 2011 13. Lanaspa MA, Ishimoto T, Cicerchi C, Tamura Y, Roncal-Jimenez CA, Chen W, Tanabe K, Andres-Hernando A, Orlicky DJ, Finol E, Inaba S, Li N, Rivard CJ, Kosugi T, Sanchez-Lozada LG, Petrash JM, Sautin YY, Ejaz AA, Kitagawa W, Garcia G, Bonthron DT, Asipu A, Diggle CP, Rodriguez-Iturbe B, Nakagawa T, Johnson RJ: Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy. J Am Soc Nephrol 25: 2526–2538, 2014 14. Guder WG, Wagner S, Wirthensohn G: Metabolic fuels along the nephron: Pathways and intracellular mechanisms of interaction. Kidney Int 29: 41–45, 1986 15. Ouali F, Djouadi F, Bastin J: Effects of fatty acids on mitochondrial betaoxidation enzyme gene expression in renal cell lines. Am J Physiol Renal Physiol 283: F328–F334, 2002

See related article, “Endogenous Fructose Production and Fructokinase Activation Mediate Renal Injury in Diabetic Nephropathy,” on pages 2526–2538.

The Life Cycle of the Kidney: Implications for CKD Robert L. Chevalier Division of Pediatric Nephrology, Department of Pediatrics, University of Virginia, Charlottesville, Virginia J Am Soc Nephrol 25: 2388–2390, 2014. doi: 10.1681/ASN.2014040380

Published online ahead of print. Publication date available at www.jasn.org. Correspondence: Dr. Robert L. Chevalier, Division of Pediatric Nephrology, Department of Pediatrics, University of Virginia, PO Box 800386, Charlottesville, VA 22908. Email: [email protected] Copyright © 2014 by the American Society of Nephrology

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The growing prevalence of CKD across the world has intensified the search for factors responsible for progressive loss of kidney function over time. In the 1980s, Brenner et al. reported that reduced nephron number results in glomerular hyperfiltration and hypertrophy, leading to maladaptive further nephron injury.1 This was followed by Barker and Bagby’s observations linking low birth weight with adult cardiovascular disease, leading to the field now recognized as “developmental origins of health and disease.”2 More recently, a bridge was created between these lines of study in recognition of the wide variation in the number of nephrons in the general population. Using an unbiased but demanding stereologic approach called the disector technique, Bertram et al. demonstrated a 12-fold range in the number of nephrons per kidney in diverse populations.3 Accumulating evidence suggests that infants born with nephron number below the median are at increased risk for CKD and cardiovascular disease in adulthood.4 Although the majority of renal failure in adults results from diabetes and hypertension, recent reports demonstrate that renal failure as a result of congenital renal disorders is more likely to develop in adulthood than childhood.5,6 In this issue of JASN, investigators from Rotterdam, The Netherlands, report two studies based on the Generation R Study, a population-based prospective cohort of healthy participants followed from fetal life through 5–8 years of age. In one study, fetal growth was measured by ultrasonography in the second and third trimesters, during which nephron number increases 50-fold.7,8 These data were correlated with renal growth and eGFR through 6 years of age in 6482 children.7 Notably, higher second-trimester fetal weight was associated with higher childhood GFR, and higher birth weight was associated with higher kidney volume and GFR.7 In the second study of 923 pregnant women and their children, fetal growth, kidney volume, and umbilical and cerebral artery blood flow were measured in the third trimester.9 These were followed by measurement of BP, kidney volume, and GFR in childhood. An increased fetal umbilical/cerebral blood flow ratio was associated with smaller childhood kidney volume and lower GFR.9 These physiologic and morphometric observations are the first to be performed sequentially from fetal through postnatal life in large numbers of healthy participants, and reveal the importance of the distribution of fetal blood flow as well as early fetal renal development in postnatal renal growth and function. Previous studies show that first-trimester fetal length smaller than expected for gestational age is associated with low birth weight and premature delivery.10 This finding, along with the association of reduced fetal growth with decreased GFR in childhood,7 suggests that early impairment of metanephric growth is a risk factor for reduced postnatal renal function. In considering the changing epidemiology of CKD throughout the life cycle, it is useful to invoke the role of evolutionary principles in the biology of populations. Genetic variation (polymorphism) is an essential substrate for the action of natural selection. It should not be surprising that the number J Am Soc Nephrol 25: 2385–2392, 2014