Understanding Podocyte Biology to Develop Novel Kidney Therapeutics
Mark A Lal, Jaakko Patrakka, Mark A Lal, Jaakko Patrakka
Abstract
Over the past two decades it has become increasing clear that injury and loss of podocytes is an early and common clinical observation presented in many forms of glomerulopathy and chronic kidney disease. Identification of disease-causing monogenic mutations in numerous podocyte-expressed genes as well as studies conducted using preclinical animal models have shown that the podocyte plays a central role in establishing kidney dysfunction. In this review, we summarize current knowledge regarding the potential for podocyte-targeted therapies and give our view on how a deeper understanding of the molecular makeup of the podocyte will enable future therapeutic interventions. Specifically, we recount some of the currently described podocentric strategies for therapy and summarize the status and evolution of various model systems used to facilitate our understanding of the molecular and functional underpinnings of podocyte biology.
Keywords: chronic kidney disease; diabetic nephropathy; glomerulus; podocyte; targeted therapy.
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References
- Reidy K, Kang HM, Hostetter T, Susztak K. Molecular mechanisms of diabetic kidney disease. J Clin Invest. (2014) 124:2333–40. 10.1172/JCI72271
- Lin JS, Susztak K. Podocytes: the weakest link in diabetic kidney disease? Curr Diab Rep. (2016) 16:45. 10.1007/s11892-016-0735-5
- Wharram BL, Goyal M, Wiggins JE, Sanden SK, Hussain S, Filipiak WE, et al. . Podocyte depletion causes glomerulosclerosis: diphtheria toxin-induced podocyte depletion in rats expressing human diphtheria toxin receptor transgene. J Am Soc Nephrol. (2005) 16:2941–52. 10.1681/ASN.2005010055
- Chen J, Chen JK, Harris RC. EGF receptor deletion in podocytes attenuates diabetic nephropathy. J Am Soc Nephrol. (2015) 26:1115–25. 10.1681/ASN.2014020192
- Mathieson PW. The podocyte as a target for therapies–new and old. Nat Rev Nephrol. (2012) 8:52–6. 10.1038/nrneph.2011.171
- Gloy J, Henger A, Fischer KG, Nitschke R, Bleich M, Mundel P, et al. . Angiotensin II modulates cellular functions of podocytes. Kidney Int Suppl. (1998) 67:S168–70. 10.1046/j.1523-1755.1998.06736.x
- Matsusaka T, Asano T, Niimura F, Kinomura M, Shimizu A, Shintani A, et al. . Angiotensin receptor blocker protection against podocyte-induced sclerosis is podocyte angiotensin II type 1 receptor-independent. Hypertension (2010) 55:967–73. 10.1161/HYPERTENSIONAHA.109.141994
- Kann M, Ettou S, Jung YL, Lenz MO, Taglienti ME, Park PJ, et al. . Genome-wide analysis of Wilms' tumor 1-controlled gene expression in podocytes reveals key regulatory mechanisms. J Am Soc Nephrol. (2015) 26:2097–104. 10.1681/ASN.2014090940
- Park J, Shrestha R, Qiu C, Kondo A, Huang S, Werth M, et al. . Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. Science (2018) 360:758–63. 10.1126/science.aar2131
- Kuppe C, van Roeyen C, Leuchtle K, Kabgani N, Vogt M, Van Zandvoort M, et al. . Investigations of glucocorticoid action in GN. J Am Soc Nephrol. (2017) 28:1408–20. 10.1681/ASN.2016010060
- Mallipattu SK, Guo Y, Revelo MP, Roa-Pena L, Miller T, Ling J, et al. . Kruppel-like factor 15 mediates glucocorticoid-induced restoration of podocyte differentiation markers. J Am Soc Nephrol. (2017) 28:166–84. 10.1681/ASN.2015060672
- Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, et al. . The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med. (2008) 14:931–8. 10.1038/nm.1857
- Mallipattu SK, He JC. The podocyte as a direct target for treatment of glomerular disease? Am J Physiol Renal Physiol. (2016) 311:F46–51. 10.1152/ajprenal.00184.2016
- Fornoni A, Sageshima J, Wei C, Merscher-Gomez S, Aguillon-Prada R, Jauregui AN, et al. . Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci Transl Med. (2011) 3:85ra46. 10.1126/scitranslmed.3002231
- Kim AH, Chung JJ, Akilesh S, Koziell A, Jain S, Hodgin JB, et al. . B cell-derived IL-4 acts on podocytes to induce proteinuria and foot process effacement. JCI Insight (2017) 2:e81836. 10.1172/jci.insight.81836
- Reiser J, von Gersdorff G, Loos M, Oh J, Asanuma K, Giardino L, et al. . Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest. (2004) 113:1390–7. 10.1172/JCI20402
- Yu CC, Fornoni A, Weins A, Hakroush S, Maiguel D, Sageshima J, et al. . Abatacept in B7-1-positive proteinuric kidney disease. N Engl J Med. (2013) 369:2416–23. 10.1056/NEJMoa1304572
- Fiorina P, Vergani A, Bassi R, Niewczas MA, Altintas MM, Pezzolesi MG, et al. . Role of podocyte B7-1 in diabetic nephropathy. J Am Soc Nephrol. (2014) 25:1415–29. 10.1681/ASN.2013050518
- Gagliardini E, Novelli R, Corna D, Zoja C, Ruggiero B, Benigni A, et al. . B7-1 is not induced in podocytes of human and experimental diabetic nephropathy. J Am Soc Nephrol. (2016) 27:999–1005. 10.1681/ASN.2015030266
- Novelli R, Gagliardini E, Ruggiero B, Benigni A, Remuzzi G. Any value of podocyte B7-1 as a biomarker in human MCD and FSGS? Am J Physiol Renal Physiol. (2016) 310:F335–41. 10.1152/ajprenal.00510.2015
- Baye E, Gallazzini M, Delville M, Legendre C, Terzi F, Canaud G. The costimulatory receptor B7-1 is not induced in injured podocytes. Kidney Int. (2016) 90:1037–44. 10.1016/j.kint.2016.06.022
- Delville M, Baye E, Durrbach A, Audard V, Kofman T, Braun L, et al. . B7-1 blockade does not improve post-transplant nephrotic syndrome caused by recurrent FSGS. J Am Soc Nephrol. (2016) 27:2520–7. 10.1681/ASN.2015091002
- Moller CC, Wei C, Altintas MM, Li J, Greka A, Ohse T, et al. . Induction of TRPC6 channel in acquired forms of proteinuric kidney disease. J Am Soc Nephrol. (2007) 18:29–36. 10.1681/ASN.2006091010
- Reiser J, Polu KR, Moller CC, Kenlan P, Altintas MM, Wei C, et al. . TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet. (2005) 37:739–44. 10.1038/ng1592
- Krall P, Canales CP, Kairath P, Carmona-Mora P, Molina J, Carpio JD, et al. . Podocyte-specific overexpression of wild type or mutant trpc6 in mice is sufficient to cause glomerular disease. PLoS ONE (2010) 5:e12859. 10.1371/journal.pone.0012859
- Kistler AD, Singh G, Altintas MM, Yu H, Fernandez IC, Gu C, et al. . Transient receptor potential channel 6 (TRPC6) protects podocytes during complement-mediated glomerular disease. J Biol Chem. (2013) 288:36598–609. 10.1074/jbc.M113.488122
- Schaldecker T, Kim S, Tarabanis C, Tian D, Hakroush S, Castonguay P, et al. . Inhibition of the TRPC5 ion channel protects the kidney filter. J Clin Invest. (2013) 123:5298–309. 10.1172/JCI71165
- Zhou Y, Castonguay P, Sidhom EH, Clark AR, Dvela-Levitt M, Kim S, et al. . A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models. Science (2017) 358:1332–6. 10.1126/science.aal4178
- Wang X, Dande RR, Yu H, Samelko B, Miller RE, Altintas MM, et al. . TRPC5 does not cause or aggravate glomerular disease. J Am Soc Nephrol. (2018) 29:409–15. 10.1681/ASN.2017060682
- Ashraf S, Gee HY, Woerner S, Xie LX, Vega-Warner V, Lovric S, et al. . ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest. (2013) 123:5179–89. 10.1172/JCI69000
- Diomedi-Camassei F, Di Giandomenico S, Santorelli FM, Caridi G, Piemonte F, Montini G, et al. . COQ2 nephropathy: a newly described inherited mitochondriopathy with primary renal involvement. J Am Soc Nephrol. (2007) 18:2773–80. 10.1681/ASN.2006080833
- Heeringa SF, Chernin G, Chaki M, Zhou W, Sloan AJ, Ji Z, et al. . COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest. (2011) 121:2013–24. 10.1172/JCI45693
- Tian X, Ishibe S. Targeting the podocyte cytoskeleton: from pathogenesis to therapy in proteinuric kidney disease. Nephrol Dial Transplant. (2016) 31:1577–83. 10.1093/ndt/gfw021
- Tryggvason K, Patrakka J, Wartiovaara J. Hereditary proteinuria syndromes and mechanisms of proteinuria. N Engl J Med. (2006) 354:1387–401. 10.1056/NEJMra052131
- Ashraf S, Kudo H, Rao J, Kikuchi A, Widmeier E, Lawson JA, et al. . Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment. Nat Commun. (2018) 9:1960. 10.1038/s41467-018-04193-w
- Schiffer M, Teng B, Gu C, Shchedrina VA, Kasaikina M, Pham VA, et al. . Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models. Nat Med. (2015) 21:601–9. 10.1038/nm.3843
- Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, et al. . Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet. (2000) 24:251–6. 10.1038/73456
- Ma X, Schwarz A, Sevilla SZ, Levin A, Hultenby K, Wernerson A, et al. . Depletion of Gprc5a promotes development of diabetic nephropathy. J Am Soc Nephrol. (2018) 29:1679–89. 10.1681/ASN.2017101135
- Lal MA, Young KW, Andag U. Targeting the podocyte to treat glomerular kidney disease. Drug Discov Today. (2015) 20:1228–34. 10.1016/j.drudis.2015.06.003
- Lee HW, Khan SQ, Faridi MH, Wei C, Tardi NJ, Altintas MM, et al. . A podocyte-based automated screening assay identifies protective small molecules. J Am Soc Nephrol. (2015) 26:2741–52. 10.1681/ASN.2014090859
- Sieber J, Wieder N, Clark A, Reitberger M, Matan S, Schoenfelder J, et al. GDC-0879, a BRAF(V600E) inhibitor, protects kidney podocytes from death. Cell Chem Biol. (2017) 15:175–84. 10.1016/j.chembiol.2017.11.006
- Tsuchida J, Matsusaka T, Ohtsuka M, Miura H, Okuno Y, Asanuma K, et al. . Establishment of nephrin reporter mice and use for chemical screening. PLoS ONE (2016) 11:e0157497. 10.1371/journal.pone.0157497
- Kindt F, Hammer E, Kemnitz S, Blumenthal A, Klemm P, Schluter R, et al. . A novel assay to assess the effect of pharmaceutical compounds on the differentiation of podocytes. Br J Pharmacol. (2017) 174:163–76. 10.1111/bph.13667
- Azeloglu EU, Hardy SV, Eungdamrong NJ, Chen Y, Jayaraman G, Chuang PY, et al. . Interconnected network motifs control podocyte morphology and kidney function. Sci Signal. (2014) 7:ra12. 10.1126/scisignal.2004621
- Perico L, Mandala M, Schieppati A, Carrara C, Rizzo P, Conti S, et al. . BRAF signaling pathway inhibition, podocyte injury, and nephrotic syndrome. Am J Kidney Dis. (2017) 70:145–50. 10.1053/j.ajkd.2016.12.013
- Yaoita E, Yoshida Y, Nameta M, Takimoto H, Fujinaka H. Induction of interdigitating cell processes in podocyte culture. Kidney Int. (2018) 93:519–24. 10.1016/j.kint.2017.06.031
- Ciampi O, Iacone R, Longaretti L, Benedetti V, Graf M, Magnone MC, et al. . Generation of functional podocytes from human induced pluripotent stem cells. Stem Cell Res. (2016) 17:130–9. 10.1016/j.scr.2016.06.001
- Freedman BS, Brooks CR, Lam AQ, Fu H, Morizane R, Agrawal V, et al. . Modelling kidney disease with CRISPR-mutant kidney organoids derived from human pluripotent epiblast spheroids. Nat Commun. (2015) 6:8715. 10.1038/ncomms9715
- Takasato M, Er PX, Chiu HS, Maier B, Baillie GJ, Ferguson C, et al. . Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature (2015) 526:564–8. 10.1038/nature15695
- Musah S, Mammoto A, Ferrante TC, Jeanty SSF, Hirano-Kobayashi M, Mammoto T, et al. . Mature induced-pluripotent-stem-cell-derived human podocytes reconstitute kidney glomerular-capillary-wall function on a chip. Nat Biomed Eng. (2017) 1:0069. 10.1038/s41551-017-0069
- Song JJ, Guyette JP, Gilpin SE, Gonzalez G, Vacanti JP, Ott HC. Regeneration and experimental orthotopic transplantation of a bioengineered kidney. Nat Med. (2013) 19:646–51. 10.1038/nm.3154
- Weavers H, Prieto-Sanchez S, Grawe F, Garcia-Lopez A, Artero R, Wilsch-Brauninger M, et al. . The insect nephrocyte is a podocyte-like cell with a filtration slit diaphragm. Nature (2009) 457:322–6. 10.1038/nature07526
- Na J, Sweetwyne MT, Park AS, Susztak K, Cagan RL. Diet-induced podocyte dysfunction in drosophila and mammals. Cell Rep. (2015) 12:636–47. 10.1016/j.celrep.2015.06.056
- Kok FO, Shin M, Ni CW, Gupta A, Grosse AS, van Impel A, et al. . Reverse genetic screening reveals poor correlation between morpholino-induced and mutant phenotypes in zebrafish. Dev Cell. (2015) 32:97–108. 10.1016/j.devcel.2014.11.018
- Zhou W, Hildebrandt F. Inducible podocyte injury and proteinuria in transgenic zebrafish. J Am Soc Nephrol. (2012) 23:1039–47. 10.1681/ASN.2011080776
- Zennaro C, Mariotti M, Carraro M, Pasqualetti S, Corbelli A, Armelloni S, et al. . Podocyte developmental defects caused by adriamycin in zebrafish embryos and larvae: a novel model of glomerular damage. PLoS ONE (2014) 9:e98131. 10.1371/journal.pone.0098131
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