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The Benefits of Tubular Proteinuria: An Evolutionary Perspective

Matias Simons

Laboratory of Epithelial Biology and Disease, Imagine Institute, Paris, France; and Imagine Institute, Université Paris- Descartes-Sorbonne Paris Cité, Paris, France

J Am Soc Nephrol 29: 710–712, 2018. doi: https://doi.org/10.1681/ASN.2017111197 Constituting more than one half of renal “accessible” for toxins delivered by serum disorder causing facial dysmorphia, mass, the proximal tubule is the main proteins. Albumin’s partners in crime are vision, and hearing problems among reabsorptive segment of the nephron. megalin (gene name: LRP2), cubilin (gene other symptoms. CUBN and AMN, Proximal tubular cells (PTCs) take up name: CUBN), and amnionless (gene however, are both causative genes for almost all macromolecules filtered name: AMN), which form a receptor Imerslund–Gräsbeck syndrome (IGS; by the neighboring glomerulus, making complex mediating most of the protein Online Mendelian Inheritance in Man: use of a dense brush border and a dedi- uptake from the luminal side. 261100). This disease is a rare autosomal cated endocytic apparatus. The energy to With all of this stress brought inside, recessive disorder initially described in achieve this tremendous task is provided why is it at all desirable for the PTCs to Scandinavia that is characterized by a se- by a high number of mitochondria that reabsorb so many proteins? It can first be lective vitamin B(12) malabsorption, re- mainly use fatty acids as metabolic fuels. argued that the proteins need to be recy- sulting in megaloblastic anemia, which The high energy demand makes PTCs cled. However, it was recently shown that is responsive to parenteral vitamin very vulnerable to ischemia, metabolic lack of megalin and cubilin does not B(12) therapy (additional reading is in dysfunction, or external toxins, such as change serum levels of albumin in ne- refs. 3 and 4). The phenotypic differ- drugs. In nephrotic syndrome or diabetic phrotic syndrome, suggesting that there ences between Donnai–Barrow syn- nephropathy, glomerular proteinuria is no significant albumin recycling.5 In drome and IGS are explained by the imposes a large burden on the PTC (Fig- how far this is true for other reabsorbed fact that megalin can act independently ure 1), with the result that PTC damage proteins remains to be determined. At of the other two proteins and has a becomes a main driver of disease pro- least for albumin, it would mean that broader tissue expression pattern.4 By gression.1 In addition to the protein almost all endocytosed protein enters contrast, cubilin and amnionless need overload, PTCs are also damaged by the lysosomal pathway for degradation. each other for surface transport and the molecules brought inside by the The resulting amino acids may be used function, and they are mainly expressed proteins, such as fatty acids or advanced for lysosomal mammalian target of ra- in the kidney and the small intestine.3,7 glycation end products. pamycin activation, which in turn, Genome-wide association studies have As early as in 1982, Moorhead et al.2 maintains PTC differentiation.6 The linked a variant in the CUBN gene with an proposed the hypothesis that lipid abnor- fatty acids released from albumin, how- increased risk for albuminuria.8 Moreover, malities contribute to the progression of ever, can be used for b-oxidation in Ovunc et al.9 identified two siblings in a kidney injury. Summarized under the mitochondria to generate ATP. The two consanguineous family with isolated pro- term “lipotoxicity,” fatty acids, particu- latter points nicely illustrate the cou- teinuria caused by a homozygous deletion larly those with saturated acyl chains, pling of endocytosis and metabolism, of one base pair in exon 53 of the CUBN were since then repeatedly reported to which is characteristic for PTC function. gene. The amount of proteinuria in these damage the PTCs and their organelles. So, what happens to PTC when the The most efficient carrier of fatty acids is uptake is downregulated? This question albumin, which possesses about seven is best answered from the human genetic Published online ahead of print. Publication date binding sites for fatty acids. The study of perspective. LRP2, CUBN,andAMN are available at www.jasn.org. rare genetic diseases and animal models all genes with mutations that cause low Correspondence: Dr. Matias Simons, Institut Imagine, have suggested that albumin not only rea- molecular weight proteinuria and albu- Institut national de la santé et de la recherche médi- fi LRP2 cale (INSERM) U1163, 24 Boulevard du Montparnasse, ches the PTC when the glomerular lter is minuria in humans. mutations 75015 Paris, Ile-de-France, France. Email: matias.simons@ leaky but to some extent, also via regular lead to Donnai–Barrow syndrome (On- institutimagine.org fi 3,4 ltration. This means that, even under line Mendelian Inheritance in Man: Copyright © 2018 by the American Society of normal conditions, the PTCs are 222448), a multisystem developmental Nephrology

710 ISSN : 1046-6673/2903-710 J Am Soc Nephrol 29: 710–712, 2018 www.jasn.org PERSPECTIVES

Figure 1. The role of proximal tubular reabsorption in normal and proteinuric conditions. On the left, normal filtration and reabsorption of proteins, protein-bound lipids and toxins (such as drugs) is depicted. Protein and lipid catabolism in lysosomes and mitochondria is important to meet energy demands of PTC. In glomerular diseases, such as nephrotic syndrome or diabetic nephropathy (DN), PTC are exposed to protein, lipid and toxin overload (middle). Particularly, saturated fatty acids bound to albumin are known to cause cell damage through endoplasmic reticulum stress. Damage may be prevented by reducing PTC uptake, e.g. in patients with CUBN/AMN mutations (right). patients was variable, ranging from com- gene, even in the heterozygous state. In- mutation.11 This mutation is the most plete absence to 2 g/24 h. Similar patients tolerance to functional variation can be common cause of cystic fibrosis, and it is with CUBN mutations have also been quantified with the probability of being primarily found in European and European- identified in our molecular diagnostic loss-of-function intolerant (pLI) met- derived populations. unit (C. Antignac, personal communica- ric.10 Low pLI scores are typically seen With mutations as old as the pre- tion). What is important to point out is for redundant genes, genes that are not Neolithic era, one is, of course, invited that neither the patients with IGS nor the required for survival or reproduction, or to ponder over any selective advantages patients with isolated proteinuria seem to genes with variants that may confer some for the heterozygous carriers. Applying show signs of renal failure, let alone to selective advantage. Despite being disease Darwinian logic to the origin of a human progress to ESRD. Although more patient genes, CUBN and AMN (but not LRP2) genetic disease that persists, we have to follow-ups are needed, this would suggest have very low pLI scores,10 suggesting that consider both genetic adaptations to an that human kidneys continue to function, damaging variants are tolerated in these ancient environment and the more despite significant urinary protein loss. two genes in humans. recent benefits of these disease alleles, With the advent of large reference ge- The mutation c.208–2A.Ginintron3 despite their negative effects. The high nome databases (ExAC10 and gnomAD), of AMN deserves particular attention. frequency of the Delta F508 CFTR mu- it has been possible to not only improve This mutation accounts for over 50% of tation has been hypothesized to arise the interpretations of specificcandidate the patients with IGS outside Scandinavia. from selective pressures generated by variants but also, determine allele fre- It is found among diverse ethnicities and cholera outbreaks or the transmission quencies in the normal population over cultures, even Muslim and Jewish fami- of diarrhea-causing agents from domes- the entire coding region of a gene of lies. Studying the flanking sequences, it ticated animals, such as bovine, to hu- interest. Here, the following rule of was possible to backdate the founder mans.12 Also, the lactase polymorphism thumb can be applied: the more essential event to around 11,600 BC in the north- arose .5000 years ago as a consequence that a gene is for survival, the fewer dam- ern Mesopotamia region.11 There is only of domestication and spread rapidly due aging variants (frameshift, stop gain, or one human mutation that is thought to be to strong positive selection.13 Although essential splicing) can be found for this older, and this is the Delta F508 CFTR the CFTR mutation may limit fluid

J Am Soc Nephrol 29: 710–712, 2018 Targeting Proximal Tubular Uptake 711 PERSPECTIVES www.jasn.org secretion in diarrhea,14 the lactase poly- limitations. I am grateful to Corinne Anti- mediated apical endocytosis. Cell Reports 8: – morphism is suggested to allow for gnac, Albert de la Chappelle, Gerd Walz, and 10 19, 2014 7. Aseem O, Barth JL, Klatt SC, Smith BT, lifelong lactose digestion.13 Qais Al-Awqati for critical reading of the Argraves WS: Cubilin expression is mono- Whatmightbetheselectiveadvantage manuscript. allelic and epigenetically augmented via of the AMN founder mutation? Re- Funding in the laboratory of M.S. is sup- PPARs. BMC Genomics 14: 405, 2013 cently, the suppression of PTC uptake ported by Fondation Bettencourt-Schüller, 8. Böger CA, Chen MH, Tin A, Olden M, by targeting LRP2 has been shown to Cystinosis Research Foundation, ATIP- Köttgen A, de Boer IH, et al.; CKDGen Con- sortium: CUBN is a gene locus for albumin- be protective against kidney damage Avenir, and l’AgenceNationaledelaRe- uria. J Am Soc Nephrol 22: 555–570, 2011 caused by nephrotoxic therapeutics, cherche NEPHROFLY grants. 9. Ovunc B, Otto EA, Vega-Warner V, Saisawat hemo- and myoglobin, and high-fat P, Ashraf S, Ramaswami G, et al.: Exome se- diet.4,15 Interestingly, in most mouse DISCLOSURES quencing reveals cubilin mutation as a single- models, LRP2 inactivation was either in- gene cause of proteinuria. J Am Soc Nephrol None. – complete or mosaic, implying that, also 22: 1815 1820, 2011 10. Lek M, Karczewski KJ, Minikel EV, Samocha KE, for humans, the renoprotective effect Banks E, Fennell T, et al.; Exome Aggregation may be achieved by the loss of only REFERENCES Consortium: Analysis of protein-coding one allele. Moreover, the CUBN gene genetic variation in 60,706 humans. Na- – has been shown to be expressed in a 1. Zoja C, Abbate M, Remuzzi G: Progression of ture 536: 285 291, 2016 monoallelic fashion in the mouse kid- renal injury toward interstitial inflammation 11. Beech CM, Liyanarachchi S, Shah NP, Sturm AC, Sadiq MF, de la Chapelle A, et al.: An- ney, which could be another evolution- and glomerular sclerosis is dependent on abnormal protein filtration. Nephrol Dial cient founder mutation is responsible for ary trick to maximize the effect in Transplant 30: 706–712, 2015 Imerslund-Gräsbeck Syndrome among di- CUBN 7 heterozygotes. 2. Moorhead JF, Chan MK, El-Nahas M, verse ethnicities. Orphanet J Rare Dis 6: 74, Proving this hypothesis will not only Varghese Z: Lipid nephrotoxicity in chronic 2011 require more vigorous phenotyping in progressive glomerular and tubulo-interstitial 12. Alfonso-Sánchez MA, Pérez-Miranda AM, CUBN AMN disease. Lancet 2: 1309–1311, 1982 García-Obregón S, Peña JA: An evolutionary animal models with or de- approach to the high frequency of the Delta fi 3. Nielsen R, Christensen EI, Birn H: Megalin ciency but also, thinking about neph- and cubilin in proximal tubule protein re- F508 CFTR mutation in European populations. – rotoxic agents present in prehistoric absorption: From experimental models to Med Hypotheses 74: 989 992, 2010 times.Onething,however,ispossibly human disease. Kidney Int 89: 58–67, 2016 13. Bersaglieri T, Sabeti PC, Patterson N, already safe to conclude from these evo- 4. Willnow TE, Christ A: Endocytic receptor Vanderploeg T, Schaffner SF, Drake JA, et al.: Genetic signatures of strong recent lutionary lessons: identifying drugs that LRP2/megalin-of holoprosencephaly and re- nal Fanconi syndrome. Pflugers Arch 469: positive selection at the lactase gene. Am J – downregulate PTC receptor complex ac- 907–916, 2017 Hum Genet 74: 1111 1120, 2004 tivity might be a good strategy for renal 5. Weyer K, Andersen PK, Schmidt K, Mollet G, 14. Gabriel SE, Brigman KN, Koller BH, Boucher diseases with PTC damage. Antignac C, Birn H, et al.: Abolishment of RC, Stutts MJ: Cystic fibrosis heterozygote re- proximal tubule albumin endocytosis does sistance to cholera toxin in the cystic fibrosis not affect plasma albumin during nephrotic mouse model. Science 266: 107–109, 1994 ACKNOWLEDGMENTS syndrome in mice [published online ahead of 15. Kuwahara S, Hosojima M, Kaneko R, Aoki H, print October 13, 2017]. Kidney Int Nakano D, Sasagawa T, et al.: Megalin- 6. Gleixner EM, Canaud G, Hermle T, Guida mediated tubuloglomerular alterations in I apologize for not having been able to cite all MC, Kretz O, Helmstädter M, et al.: V-AT- high-fat diet-induced kidney disease. JAm oftheworkrelevanttothisarticleduetospace Pase/mTOR signaling regulates megalin- Soc Nephrol 27: 1996–2008, 2015

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