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Targeting angiogenesis and lymphangiogenesis in kidney disease

Nature Reviews Nephrology volume 16, pages 289–303 (2020)Cite this article

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Abstract

The kidney is permeated by a highly complex vascular system with glomerular and peritubular capillary networks that are essential for maintaining the normal functions of glomerular and tubular epithelial cells. The integrity of the renal vascular network depends on a balance of proangiogenic and antiangiogenic factors, and disruption of this balance has been identified in various kidney diseases. Decreased levels of the predominant proangiogenic factor, vascular endothelial growth factor A (VEGFA), can result in glomerular microangiopathy and contribute to the onset of preeclampsia, whereas upregulation of VEGFA has roles in diabetic kidney disease (DKD) and polycystic kidney disease (PKD). Other factors that regulate angiogenesis, such as angiopoietin 1 and vasohibin 1, have been shown to be protective in animal models of DKD and renal fibrosis. The renal lymphatic system is important for fluid homeostasis in the kidney, as well as the transport of immune cells and antigens. Experimental studies suggest that the lymphangiogenic factor VEGFC might have protective effects in PKD, DKD and renal fibrosis. Understanding the physiological and pathological roles of factors that regulate angiogenesis and lymphangiogenesis in the kidney has led to the development of novel therapeutic strategies for kidney diseases.

Key points

  • In the kidney, the glomerular and peritubular capillary networks are critical for normal nephron function; disruption of these networks can lead to the development and progression of various kidney diseases.

  • Normal expression of the proangiogenic factor vascular endothelial growth factor A (VEGFA), the vascular maturation factor angiopoietin 1 and the antiangiogenic factor vasohibin 1 is essential for maintaining capillary networks in the kidney.

  • The expression of proangiogenic and antiangiogenic factors can be altered in kidney diseases, including diabetic kidney disease (DKD) and renal fibrosis; targeting these factors is considered a promising therapeutic strategy.

  • Formation of abnormal lymphatic vessel networks accompanied by inflammatory infiltration is associated with various kidney diseases.

  • Experimental studies suggest that administration of VEGFC — the main regulator of lymphangiogenesis — might be beneficial in DKD, renal fibrosis and polycystic kidney disease.

  • Novel approaches to selectively delivering angiogenesis-regulating factors to the placenta and kidney have been developed as therapeutic strategies for preeclampsia and renovascular disease, respectively.

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Fig. 1: The renal vascular system and capillary networks.
Fig. 2: Key factors that regulate angiogenesis and promote endothelial cell survival.
Fig. 3: TGFβ-induced angiogenesis in endothelial cells.
Fig. 4: The lymphatic vasculature in the renal cortex.
Fig. 5: VEGFC-mediated regulation of lymphangiogenesis and angiogenesis.
Fig. 6: Pathological roles of factors that regulate angiogenesis and lymphangiogenesis in diabetic kidney disease.
Fig. 7: Roles of factors that regulate angiogenesis and lymphangiogenesis in the progression of tubulointerstitial fibrosis.

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References

  1. Webster, A. C., Nagler, E. V., Morton, R. L. & Masson, P. Chronic kidney disease. Lancet 389, 1238–1252 (2017).

    PubMed  Google Scholar 

  2. Kida, Y., Tchao, B. N. & Yamaguchi, I. Peritubular capillary rarefaction: a new therapeutic target in chronic kidney disease. Pediatr. Nephrol. 29, 333–342 (2014).

    PubMed  Google Scholar 

  3. Babickova, J. et al. Regardless of etiology, progressive renal disease causes ultrastructural and functional alterations of peritubular capillaries. Kidney Int. 91, 70–85 (2017).

    CAS  PubMed  Google Scholar 

  4. Tanaka, T. & Nangaku, M. Angiogenesis and hypoxia in the kidney. Nat. Rev. Nephrol. 9, 211–222 (2013).

    CAS  PubMed  Google Scholar 

  5. Zuazo-Gaztelu, I. & Casanovas, O. Unraveling the role of angiogenesis in cancer ecosystems. Front. Oncol. 8, 248 (2018).

    PubMed  PubMed Central  Google Scholar 

  6. De Palma, M., Biziato, D. & Petrova, T. V. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 17, 457–474 (2017).

    PubMed  Google Scholar 

  7. Lugano, R., Ramachandran, M. & Dimberg, A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell. Mol. Life Sci. https://doi.org/10.1007/s00018-019-03351-7 (2019).

    Article  PubMed  Google Scholar 

  8. Apte, R. S., Chen, D. S. & Ferrara, N. VEGF in signaling and disease: beyond discovery and development. Cell 176, 1248–1264 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Eremina, V. et al. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. J. Clin. Invest. 111, 707–716 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Eremina, V. et al. VEGF inhibition and renal thrombotic microangiopathy. N. Engl. J. Med. 358, 1129–1136 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Russell, P. S., Hong, J., Windsor, J. A., Itkin, M. & Phillips, A. R. J. Renal lymphatics: anatomy, physiology, and clinical implications. Front. Physiol. 10, 251 (2019).

    PubMed  PubMed Central  Google Scholar 

  12. Rauniyar, K., Jha, S. K. & Jeltsch, M. Biology of vascular endothelial growth factor C in the morphogenesis of lymphatic vessels. Front. Bioeng. Biotechnol. 6, 7 (2018).

    PubMed  PubMed Central  Google Scholar 

  13. Graves, F. T. The anatomy of the intrarenal arteries and its application to segmental resection of the kidney. Br. J. Surg. 42, 132–139 (1954).

    CAS  PubMed  Google Scholar 

  14. Macchi, V. et al. Anatomical study of renal arterial vasculature and its potential impact on partial nephrectomy. BJU Int. 120, 83–91 (2017).

    CAS  PubMed  Google Scholar 

  15. Dimke, H., Maezawa, Y. & Quaggin, S. E. Crosstalk in glomerular injury and repair. Curr. Opin. Nephrol. Hypertens. 24, 231–238 (2015).

    PubMed  PubMed Central  Google Scholar 

  16. Chade, A. R. Small vessels, big role: renal microcirculation and progression of renal injury. Hypertension 69, 551–563 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Tanabe, K., Maeshima, Y., Sato, Y. & Wada, J. Antiangiogenic therapy for diabetic nephropathy. Biomed Res. Int. 2017, 5724069 (2017).

    PubMed  PubMed Central  Google Scholar 

  18. Simons, M., Gordon, E. & Claesson-Welsh, L. Mechanisms and regulation of endothelial VEGF receptor signalling. Nat. Rev. Mol. Cell Biol. 17, 611–625 (2016).

    CAS  PubMed  Google Scholar 

  19. Tanabe, K., Sato, Y. & Wada, J. Endogenous antiangiogenic factors in chronic kidney disease: potential biomarkers of progression. Int. J. Mol. Sci. 19, 1859 (2018).

    PubMed Central  Google Scholar 

  20. Peach, C. J. et al. Molecular pharmacology of VEGF-A isoforms: binding and signalling at VEGFR2. Int. J. Mol. Sci. 19, 1264 (2018).

    PubMed Central  Google Scholar 

  21. Guo, H. F. & Vander Kooi, C. W. Neuropilin functions as an essential cell surface receptor. J. Biol. Chem. 290, 29120–29126 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Brown, L. F. et al. Vascular permeability factor mRNA and protein expression in human kidney. Kidney Int. 42, 1457–1461 (1992).

    CAS  PubMed  Google Scholar 

  23. Kanellis, J., Mudge, S. J., Fraser, S., Katerelos, M. & Power, D. A. Redistribution of cytoplasmic VEGF to the basolateral aspect of renal tubular cells in ischemia-reperfusion injury. Kidney Int. 57, 2445–2456 (2000).

    CAS  PubMed  Google Scholar 

  24. Wu, S., Kim, C., Baer, L. & Zhu, X. Bevacizumab increases risk for severe proteinuria in cancer patients. J. Am. Soc. Nephrol. 21, 1381–1389 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Moslehi, J. J. Cardiovascular toxic effects of targeted cancer therapies. N. Engl. J. Med. 375, 1457–1467 (2016).

    CAS  PubMed  Google Scholar 

  26. Person, F. et al. Bevacizumab-associated glomerular microangiopathy. Mod. Pathol. 32, 684–700 (2019).

    CAS  PubMed  Google Scholar 

  27. Kandula, P. & Agarwal, R. Proteinuria and hypertension with tyrosine kinase inhibitors. Kidney Int. 80, 1271–1277 (2011).

    CAS  PubMed  Google Scholar 

  28. Izzedine, H. et al. Kidney diseases associated with anti-vascular endothelial growth factor (VEGF): an 8-year observational study at a single center. Medicine 93, 333–339 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Estrada, C. C., Maldonado, A. & Mallipattu, S. K. Therapeutic inhibition of VEGF signaling and associated nephrotoxicities. J. Am. Soc. Nephrol. 30, 187–200 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Dimke, H. et al. Tubulovascular cross-talk by vascular endothelial growth factor a maintains peritubular microvasculature in kidney. J. Am. Soc. Nephrol. 26, 1027–1038 (2015).

    CAS  PubMed  Google Scholar 

  31. Hakroush, S. et al. Effects of increased renal tubular vascular endothelial growth factor (VEGF) on fibrosis, cyst formation, and glomerular disease. Am. J. Pathol. 175, 1883–1895 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Roth, L. et al. Neuropilin-1 mediates vascular permeability independently of vascular endothelial growth factor receptor-2 activation. Sci. Signal. 9, ra42 (2016).

    PubMed  Google Scholar 

  33. Aggarwal, P. K. et al. Semaphorin3a promotes advanced diabetic nephropathy. Diabetes 64, 1743–1759 (2015).

    CAS  PubMed  Google Scholar 

  34. Sawamiphak, S. et al. Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature 465, 487–491 (2010).

    CAS  PubMed  Google Scholar 

  35. Kida, Y., Ieronimakis, N., Schrimpf, C., Reyes, M. & Duffield, J. S. EphrinB2 reverse signaling protects against capillary rarefaction and fibrosis after kidney injury. J. Am. Soc. Nephrol. 24, 559–572 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Becerra, S. P. & Notario, V. The effects of PEDF on cancer biology: mechanisms of action and therapeutic potential. Nat. Rev. Cancer 13, 258–271 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Fujimura, T. et al. Administration of pigment epithelium-derived factor (PEDF) reduces proteinuria by suppressing decreased nephrin and increased VEGF expression in the glomeruli of adriamycin-injected rats. Nephrol. Dial. Transplant. 24, 1397–1406 (2009).

    CAS  PubMed  Google Scholar 

  38. Saharinen, P., Eklund, L. & Alitalo, K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat. Rev. Drug. Discov. 16, 635–661 (2017).

    CAS  PubMed  Google Scholar 

  39. Woolf, A. S., Gnudi, L. & Long, D. A. Roles of angiopoietins in kidney development and disease. J. Am. Soc. Nephrol. 20, 239–244 (2009).

    CAS  PubMed  Google Scholar 

  40. Parikh, S. M. The angiopoietin-Tie2 signaling axis in systemic inflammation. J. Am. Soc. Nephrol. 28, 1973–1982 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Winderlich, M. et al. VE-PTP controls blood vessel development by balancing Tie-2 activity. J. Cell Biol. 185, 657–671 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Souma, T. et al. Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP. Proc. Natl Acad. Sci. USA 115, 1298–1303 (2018).

    CAS  PubMed  Google Scholar 

  43. Bafunno, V. et al. Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema. J. Allergy Clin. Immunol. 141, 1009–1017 (2018).

    CAS  PubMed  Google Scholar 

  44. d’Apolito, M. et al. Angiopoietin-1 haploinsufficiency affects the endothelial barrier and causes hereditary angioedema. Clin. Exp. Allergy 49, 626–635 (2019).

    PubMed  Google Scholar 

  45. Yuan, H. T., Suri, C., Yancopoulos, G. D. & Woolf, A. S. Expression of angiopoietin-1, angiopoietin-2, and the Tie-2 receptor tyrosine kinase during mouse kidney maturation. J. Am. Soc. Nephrol. 10, 1722–1736 (1999).

    CAS  PubMed  Google Scholar 

  46. Jeansson, M. et al. Angiopoietin-1 is essential in mouse vasculature during development and in response to injury. J. Clin. Invest. 121, 2278–2289 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Loganathan, K. et al. Angiopoietin-1 deficiency increases renal capillary rarefaction and tubulointerstitial fibrosis in mice. PLoS One 13, e0189433 (2018).

    PubMed  PubMed Central  Google Scholar 

  48. Kenig-Kozlovsky, Y. et al. Ascending vasa recta are angiopoietin/Tie2-dependent lymphatic-like vessels. J. Am. Soc. Nephrol. 29, 1097–1107 (2018).

    CAS  PubMed  Google Scholar 

  49. Davis, B. et al. Podocyte-specific expression of angiopoietin-2 causes proteinuria and apoptosis of glomerular endothelia. J. Am. Soc. Nephrol. 18, 2320–2329 (2007).

    CAS  PubMed  Google Scholar 

  50. Allegretti, A. S. et al. Serum angiopoietin-2 predicts mortality and kidney outcomes in decompensated cirrhosis. Hepatology 69, 729–741 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Araujo, C. B. et al. Angiopoietin-2 as a predictor of acute kidney injury in critically ill patients and association with ARDS. Respirology 24, 345–351 (2019).

    PubMed  Google Scholar 

  52. El-Kenawi, A. E. & El-Remessy, A. B. Angiogenesis inhibitors in cancer therapy: mechanistic perspective on classification and treatment rationales. Br. J. Pharmacol. 170, 712–729 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Walia, A. et al. Endostatin’s emerging roles in angiogenesis, lymphangiogenesis, disease, and clinical applications. Biochim. Biophys. Acta 1850, 2422–2438 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Marneros, A. G. & Olsen, B. R. Physiological role of collagen XVIII and endostatin. FASEB J. 19, 716–728 (2005).

    CAS  PubMed  Google Scholar 

  55. Utriainen, A. et al. Structurally altered basement membranes and hydrocephalus in a type XVIII collagen deficient mouse line. Hum. Mol. Genet. 13, 2089–2099 (2004).

    CAS  PubMed  Google Scholar 

  56. Hamano, Y. et al. Lack of collagen XVIII/endostatin exacerbates immune-mediated glomerulonephritis. J. Am. Soc. Nephrol. 21, 1445–1455 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Chauhan, K. et al. Plasma endostatin predicts kidney outcomes in patients with type 2 diabetes. Kidney Int. 95, 439–446 (2019).

    CAS  PubMed  Google Scholar 

  58. Watanabe, K. et al. Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis. J. Clin. Invest. 114, 898–907 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Miyashita, H. et al. Angiogenesis inhibitor vasohibin-1 enhances stress resistance of endothelial cells via induction of SOD2 and SIRT1. PLoS One 7, e46459 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kimura, H. et al. Distinctive localization and opposed roles of vasohibin-1 and vasohibin-2 in the regulation of angiogenesis. Blood 113, 4810–4818 (2009).

    CAS  PubMed  Google Scholar 

  61. Hosaka, T. et al. Vasohibin-1 expression in endothelium of tumor blood vessels regulates angiogenesis. Am. J. Pathol. 175, 430–439 (2009).

    PubMed  PubMed Central  Google Scholar 

  62. Koyanagi, T. et al. Downregulation of vasohibin-2, a novel angiogenesis regulator, suppresses tumor growth by inhibiting angiogenesis in endometrial cancer cells. Oncol. Lett. 5, 1058–1062 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Olmer, R. et al. Long term expansion of undifferentiated human iPS and ES cells in suspension culture using a defined medium. Stem Cell Res. 5, 51–64 (2010).

    CAS  PubMed  Google Scholar 

  64. Norita, R. et al. Vasohibin-2 is required for epithelial-mesenchymal transition of ovarian cancer cells by modulating transforming growth factor-beta signaling. Cancer Sci. 108, 419–426 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Takeda, E., Suzuki, Y., Yamada, T., Katagiri, H. & Sato, Y. Knockout of vasohibin-1 gene in mice results in healthy longevity with reduced expression of insulin receptor, insulin receptor substrate 1, and insulin receptor substrate 2 in their white adipose tissue. J. Aging Res. 2017, 9851380 (2017).

    PubMed  PubMed Central  Google Scholar 

  66. Tanimura, S. et al. Renal tubular injury exacerbated by vasohibin-1 deficiency in a murine cisplatin-induced acute kidney injury model. Am. J. Physiol. Renal Physiol. 317, F264–F274 (2019).

    CAS  PubMed  Google Scholar 

  67. Masuda, K. et al. Deletion of pro-angiogenic factor vasohibin-2 ameliorates glomerular alterations in a mouse diabetic nephropathy model. PLoS One 13, e0195779 (2018).

    PubMed  PubMed Central  Google Scholar 

  68. Hinamoto, N. et al. Urinary and plasma levels of vasohibin-1 can predict renal functional deterioration in patients with renal disorders. PLoS One 9, e96932 (2014).

    PubMed  PubMed Central  Google Scholar 

  69. Ren, H. et al. Expression levels of serum vasohibin-1 and other biomarkers in type 2 diabetes mellitus patients with different urinary albumin to creatinine ratios. J. Diabetes Complicat. 33, 477–484 (2019).

    PubMed  Google Scholar 

  70. Meng, X. M., Nikolic-Paterson, D. J. & Lan, H. Y. TGF-beta: the master regulator of fibrosis. Nat. Rev. Nephrol. 12, 325–338 (2016).

    CAS  PubMed  Google Scholar 

  71. Pardali, E., Goumans, M. J. & ten Dijke, P. Signaling by members of the TGF-beta family in vascular morphogenesis and disease. Trends Cell Biol. 20, 556–567 (2010).

    CAS  PubMed  Google Scholar 

  72. Cunha, S. I. & Pietras, K. ALK1 as an emerging target for antiangiogenic therapy of cancer. Blood 117, 6999–7006 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Lopez-Novoa, J. M. & Bernabeu, C. The physiological role of endoglin in the cardiovascular system. Am. J. Physiol. Heart Circ. Physiol. 299, H959–H974 (2010).

    CAS  PubMed  Google Scholar 

  74. Ruiz-Llorente, L. et al. Endoglin and alk1 as therapeutic targets for hereditary hemorrhagic telangiectasia. Expert. Opin. Ther. Targets 21, 933–947 (2017).

    CAS  PubMed  Google Scholar 

  75. Wang, X. et al. LRG1 promotes angiogenesis by modulating endothelial TGF-beta signalling. Nature 499, 306–311 (2013).

    CAS  PubMed  Google Scholar 

  76. Haku, S. et al. Early enhanced leucine-rich alpha-2-glycoprotein-1 expression in glomerular endothelial cells of type 2 diabetic nephropathy model mice. Biomed Res. Int. 2018, 2817045 (2018).

    PubMed  PubMed Central  Google Scholar 

  77. Hong, Q. et al. LRG1 promotes diabetic kidney disease progression by enhancing TGF-beta-induced angiogenesis. J. Am. Soc. Nephrol. 30, 546–562 (2019).

    PubMed  PubMed Central  Google Scholar 

  78. Karaman, S., Leppanen, V. M. & Alitalo, K. Vascular endothelial growth factor signaling in development and disease. Development 145, dev.151019 (2018).

    Google Scholar 

  79. Jha, S. K. et al. KLK3/PSA and cathepsin D activate VEGF-C and VEGF-D. eLife 8, e44478 (2019).

    PubMed  PubMed Central  Google Scholar 

  80. Dellinger, M. T., Hunter, R. J., Bernas, M. J., Witte, M. H. & Erickson, R. P. Chy-3 mice are Vegfc haploinsufficient and exhibit defective dermal superficial to deep lymphatic transition and dermal lymphatic hypoplasia. Dev. Dyn. 236, 2346–2355 (2007).

    CAS  PubMed  Google Scholar 

  81. Balboa-Beltran, E. et al. A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease. J. Med. Genet. 51, 475–478 (2014).

    CAS  PubMed  Google Scholar 

  82. Nurmi, H. et al. VEGF-C is required for intestinal lymphatic vessel maintenance and lipid absorption. EMBO Mol. Med. 7, 1418–1425 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Baldwin, M. E. et al. Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol. Cell. Biol. 25, 2441–2449 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Koch, M. et al. VEGF-D deficiency in mice does not affect embryonic or postnatal lymphangiogenesis but reduces lymphatic metastasis. J. Pathol. 219, 356–364 (2009).

    CAS  PubMed  Google Scholar 

  85. Haiko, P. et al. Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos. Mol. Cell. Biol. 28, 4843–4850 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Zarjou, A. et al. Dynamic signature of lymphangiogenesis during acute kidney injury and chronic kidney disease. Lab. Invest. 99, 1376–1388 (2019).

    PubMed  PubMed Central  Google Scholar 

  87. Foster, R. R. et al. VEGF-C promotes survival in podocytes. Am. J. Physiol. Renal Physiol. 291, F196–F207 (2006).

    CAS  PubMed  Google Scholar 

  88. Foster, R. R. et al. Vascular endothelial growth factor-C, a potential paracrine regulator of glomerular permeability, increases glomerular endothelial cell monolayer integrity and intracellular calcium. Am. J. Pathol. 173, 938–948 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Bartlett, C. S., Jeansson, M. & Quaggin, S. E. Vascular growth factors and glomerular disease. Annu. Rev. Physiol. 78, 437–461 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Armaly, Z., Jadaon, J. E., Jabbour, A. & Abassi, Z. A. Preeclampsia: novel mechanisms and potential therapeutic approaches. Front. Physiol. 9, 973 (2018).

    PubMed  PubMed Central  Google Scholar 

  91. Stillman, I. E. & Karumanchi, S. A. The glomerular injury of preeclampsia. J. Am. Soc. Nephrol. 18, 2281–2284 (2007).

    PubMed  Google Scholar 

  92. Levine, R. J. et al. Circulating angiogenic factors and the risk of preeclampsia. N. Engl. J. Med. 350, 672–683 (2004).

    CAS  PubMed  Google Scholar 

  93. Agrawal, S., Cerdeira, A. S., Redman, C. & Vatish, M. Meta-analysis and systematic review to assess the role of soluble FMS-like tyrosine kinase-1 and placenta growth factor ratio in prediction of preeclampsia: the SaPPPhirE study. Hypertension 71, 306–316 (2018).

    CAS  PubMed  Google Scholar 

  94. Zeisler, H. et al. Predictive value of the sFlt-1:PlGF ratio in women with suspected preeclampsia. N. Engl. J. Med. 374, 13–22 (2016).

    CAS  PubMed  Google Scholar 

  95. Rana, S., Lemoine, E., Granger, J. & Karumanchi, S. A. Preeclampsia: pathophysiology, challenges, and perspectives. Circ. Res. 124, 1094–1112 (2019).

    CAS  PubMed  Google Scholar 

  96. Spradley, F. T. et al. Placental growth factor administration abolishes placental ischemia-induced hypertension. Hypertension 67, 740–747 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Makris, A. et al. Placental growth factor reduces blood pressure in a uteroplacental ischemia model of preeclampsia in nonhuman primates. Hypertension 67, 1263–1272 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Ren, Z., Cui, N., Zhu, M. & Khalil, R. A. Placental growth factor reverses decreased vascular and uteroplacental MMP-2 and MMP-9 and increased MMP-1 and MMP-7 and collagen types I and IV in hypertensive pregnancy. Am. J. Physiol. Heart Circ. Physiol. 315, H33–H47 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Logue, O. C., Mahdi, F., Chapman, H., George, E. M. & Bidwell, G. L., III. A maternally sequestered, biopolymer-stabilized vascular endothelial growth factor (VEGF) chimera for treatment of preeclampsia. J. Am. Heart Assoc. 6, e007216 (2017).

    PubMed  PubMed Central  Google Scholar 

  100. Parchem, J. G. et al. Loss of placental growth factor ameliorates maternal hypertension and preeclampsia in mice. J. Clin. Invest. 128, 5008–5017 (2018).

    PubMed  PubMed Central  Google Scholar 

  101. Bergmann, A. et al. Reduction of circulating soluble Flt-1 alleviates preeclampsia-like symptoms in a mouse model. J. Cell. Mol. Med. 14, 1857–1867 (2010).

    CAS  PubMed  Google Scholar 

  102. Jin, J. et al. Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function. Cell 151, 384–399 (2012).

    CAS  PubMed  Google Scholar 

  103. Turanov, A. A. et al. RNAi modulation of placental sFLT1 for the treatment of preeclampsia. Nat. Biotechnol. 36, 1164–1173 (2018).

    CAS  Google Scholar 

  104. Robertson, S. A. Preventing preeclampsia by silencing soluble Flt-1? N. Engl. J. Med. 380, 1080–1082 (2019).

    PubMed  Google Scholar 

  105. Trapiella-Alfonso, L. et al. VEGF (vascular endothelial growth factor) functionalized magnetic beads in a microfluidic device to improve the angiogenic balance in preeclampsia. Hypertension 74, 145–153 (2019).

    CAS  PubMed  Google Scholar 

  106. Brenner, B. M. et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med. 345, 861–869 (2001).

    CAS  PubMed  Google Scholar 

  107. Perkovic, V. et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N. Engl. J. Med. 380, 2295–2306 (2019).

    CAS  PubMed  Google Scholar 

  108. Tervaert, T. W. et al. Pathologic classification of diabetic nephropathy. J. Am. Soc. Nephrol. 21, 556–563 (2010).

    PubMed  Google Scholar 

  109. Reidy, K., Kang, H. M., Hostetter, T. & Susztak, K. Molecular mechanisms of diabetic kidney disease. J. Clin. Invest. 124, 2333–2340 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Nakagawa, T. et al. Endothelial dysfunction as a potential contributor in diabetic nephropathy. Nat. Rev. Nephrol. 7, 36–44 (2011).

    PubMed  Google Scholar 

  111. Nakagawa, T. et al. Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. J. Am. Soc. Nephrol. 18, 539–550 (2007).

    CAS  PubMed  Google Scholar 

  112. Mohan, S. et al. Diabetic eNOS knockout mice develop distinct macro- and microvascular complications. Lab. Invest. 88, 515–528 (2008).

    CAS  PubMed  Google Scholar 

  113. Kanesaki, Y. et al. Vascular endothelial growth factor gene expression is correlated with glomerular neovascularization in human diabetic nephropathy. Am. J. Kidney Dis. 45, 288–294 (2005).

    CAS  PubMed  Google Scholar 

  114. Veron, D. et al. Podocyte vascular endothelial growth factor (VEGF(1)(6)(4)) overexpression causes severe nodular glomerulosclerosis in a mouse model of type 1 diabetes. Diabetologia 54, 1227–1241 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Veron, D. et al. Podocyte-specific VEGF-a gain of function induces nodular glomerulosclerosis in eNOS null mice. J. Am. Soc. Nephrol. 25, 1814–1824 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Baelde, H. J. et al. Reduction of VEGF-A and CTGF expression in diabetic nephropathy is associated with podocyte loss. Kidney Int. 71, 637–645 (2007).

    CAS  PubMed  Google Scholar 

  117. Sivaskandarajah, G. A. et al. Vegfa protects the glomerular microvasculature in diabetes. Diabetes 61, 2958–2966 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Dessapt-Baradez, C. et al. Targeted glomerular angiopoietin-1 therapy for early diabetic kidney disease. J. Am. Soc. Nephrol. 25, 33–42 (2014).

    CAS  PubMed  Google Scholar 

  119. Carota, I. A. et al. Targeting VE-PTP phosphatase protects the kidney from diabetic injury. J. Exp. Med. 216, 936–949 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Hinamoto, N. et al. Exacerbation of diabetic renal alterations in mice lacking vasohibin-1. PLoS One 9, e107934 (2014).

    PubMed  PubMed Central  Google Scholar 

  121. Nasu, T. et al. Vasohibin-1, a negative feedback regulator of angiogenesis, ameliorates renal alterations in a mouse model of diabetic nephropathy. Diabetes 58, 2365–2375 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Bus, P. et al. Endoglin mediates vascular endothelial growth factor-A-induced endothelial cell activation by regulating Akt signaling. Am. J. Pathol. 188, 2924–2935 (2018).

    CAS  PubMed  Google Scholar 

  123. Onions, K. L. et al. VEGFC reduces glomerular albumin permeability and protects against alterations in VEGF receptor expression in diabetic nephropathy. Diabetes 68, 172–187 (2019).

    CAS  PubMed  Google Scholar 

  124. Floege, J. & Amann, K. Primary glomerulonephritides. Lancet 387, 2036–2048 (2016).

    PubMed  Google Scholar 

  125. Avihingsanon, Y. et al. Decreased renal expression of vascular endothelial growth factor in lupus nephritis is associated with worse prognosis. Kidney Int. 75, 1340–1348 (2009).

    CAS  PubMed  Google Scholar 

  126. Sato, W. et al. The pivotal role of VEGF on glomerular macrophage infiltration in advanced diabetic nephropathy. Lab. Invest. 88, 949–961 (2008).

    CAS  PubMed  Google Scholar 

  127. Keir, L. S. et al. VEGF regulates local inhibitory complement proteins in the eye and kidney. J. Clin. Invest. 127, 199–214 (2017).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  129. Glassock, R. J. & Rule, A. D. The implications of anatomical and functional changes of the aging kidney: with an emphasis on the glomeruli. Kidney Int. 82, 270–277 (2012).

    PubMed  PubMed Central  Google Scholar 

  130. Leonard, E. C., Friedrich, J. L. & Basile, D. P. VEGF-121 preserves renal microvessel structure and ameliorates secondary renal disease following acute kidney injury. Am. J. Physiol. Renal Physiol. 295, F1648–F1657 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Basile, D. P. et al. Impaired endothelial proliferation and mesenchymal transition contribute to vascular rarefaction following acute kidney injury. Am. J. Physiol. Renal Physiol. 300, F721–F733 (2011).

    CAS  PubMed  Google Scholar 

  132. Liu, E. et al. Increased expression of vascular endothelial growth factor in kidney leads to progressive impairment of glomerular functions. J. Am. Soc. Nephrol. 18, 2094–2104 (2007).

    CAS  PubMed  Google Scholar 

  133. Singh, S. et al. Tubular overexpression of angiopoietin-1 attenuates renal fibrosis. PLoS One 11, e0158908 (2016).

    PubMed  PubMed Central  Google Scholar 

  134. Takeda, E., Suzuki, Y. & Sato, Y. Age-associated downregulation of vasohibin-1 in vascular endothelial cells. Aging Cell 15, 885–892 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Watatani, H. et al. Vasohibin-1 deficiency enhances renal fibrosis and inflammation after unilateral ureteral obstruction. Physiol. Rep. 2 (2014).

  136. Lee, A. S. et al. Vascular endothelial growth factor-C and -D are involved in lymphangiogenesis in mouse unilateral ureteral obstruction. Kidney Int. 83, 50–62 (2013).

    CAS  PubMed  Google Scholar 

  137. Kinashi, H. et al. Connective tissue growth factor regulates fibrosis-associated renal lymphangiogenesis. Kidney Int. 92, 850–863 (2017).

    CAS  PubMed  Google Scholar 

  138. Schwager, S. & Detmar, M. Inflammation and lymphatic function. Front. Immunol. 10, 308 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Hasegawa, S. et al. Vascular endothelial growth factor-C ameliorates renal interstitial fibrosis through lymphangiogenesis in mouse unilateral ureteral obstruction. Lab. Invest. 97, 1439–1452 (2017).

    PubMed  Google Scholar 

  140. Ruge, T. et al. Endostatin level is associated with kidney injury in the elderly: findings from two community-based cohorts. Am. J. Nephrol. 40, 417–424 (2014).

    CAS  PubMed  Google Scholar 

  141. Lin, C. H. et al. Endostatin and kidney fibrosis in aging: a case for antagonistic pleiotropy? Am. J. Physiol. Heart Circ. Physiol. 306, H1692–H1699 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Faye, C. et al. Transglutaminase-2: a new endostatin partner in the extracellular matrix of endothelial cells. Biochem. J. 427, 467–475 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Lin, C. H. et al. Endostatin and transglutaminase 2 are involved in fibrosis of the aging kidney. Kidney Int. 89, 1281–1292 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Leonhard, W. N., Happe, H. & Peters, D. J. Variable cyst development in autosomal dominant polycystic kidney disease: the biologic context. J. Am. Soc. Nephrol. 27, 3530–3538 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Wei, W., Popov, V., Walocha, J. A., Wen, J. & Bello-Reuss, E. Evidence of angiogenesis and microvascular regression in autosomal-dominant polycystic kidney disease kidneys: a corrosion cast study. Kidney Int. 70, 1261–1268 (2006).

    CAS  PubMed  Google Scholar 

  146. Suwabe, T. et al. Suitability of patients with autosomal dominant polycystic kidney disease for renal transcatheter arterial embolization. J. Am. Soc. Nephrol. 27, 2177–2187 (2016).

    CAS  PubMed  Google Scholar 

  147. Song, X. et al. Systems biology of autosomal dominant polycystic kidney disease (ADPKD): computational identification of gene expression pathways and integrated regulatory networks. Hum. Mol. Genet. 18, 2328–2343 (2009).

    CAS  PubMed  Google Scholar 

  148. Tao, Y. et al. VEGF receptor inhibition slows the progression of polycystic kidney disease. Kidney Int. 72, 1358–1366 (2007).

    CAS  PubMed  Google Scholar 

  149. Raina, S. et al. Anti-VEGF antibody treatment accelerates polycystic kidney disease. Am. J. Physiol. Renal Physiol. 301, F773–F783 (2011).

    CAS  PubMed  Google Scholar 

  150. Huang, J. L. et al. Vascular endothelial growth factor C for polycystic kidney diseases. J. Am. Soc. Nephrol. 27, 69–77 (2016).

    CAS  PubMed  Google Scholar 

  151. Chade, A. R. Renovascular disease, microcirculation, and the progression of renal injury: role of angiogenesis. Am. J. Physiol. Regulatory, Integr. Comp. Physiol. 300, R783–R790 (2011).

    CAS  Google Scholar 

  152. Cooper, C. J. et al. Stenting and medical therapy for atherosclerotic renal-artery stenosis. N. Engl. J. Med. 370, 13–22 (2014).

    CAS  PubMed  Google Scholar 

  153. Eirin, A. et al. Mesenchymal stem cell-derived extracellular vesicles attenuate kidney inflammation. Kidney Int. 92, 114–124 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Eirin, A. et al. Mesenchymal stem cell-derived extracellular vesicles improve the renal microvasculature in metabolic renovascular disease in swine. Cell Transplant. 27, 1080–1095 (2018).

    PubMed  PubMed Central  Google Scholar 

  155. Chade, A. R. et al. Systemic biopolymer-delivered vascular endothelial growth factor promotes therapeutic angiogenesis in experimental renovascular disease. Kidney Int. 93, 842–854 (2018).

    CAS  PubMed  Google Scholar 

  156. Bidwell, G. L., 3rd et al. A kidney-selective biopolymer for targeted drug delivery. Am. J. Physiol. Renal Physiol. 312, F54–F64 (2017).

    CAS  PubMed  Google Scholar 

  157. Engel, J. E., Williams, E., Williams, M. L., Bidwell, G. L., 3rd & Chade, A. R. Targeted VEGF (vascular endothelial growth factor) therapy induces long-term renal recovery in chronic kidney disease via macrophage polarization. Hypertension 74, 1113–1123 (2019).

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Katsuyuki Tanabe & Jun Wada

  2. New Industry Creation Hatchery Center, Tohoku University, Sendai, Japan

    Yasufumi Sato

Authors
  1. Katsuyuki Tanabe
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  2. Jun Wada
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  3. Yasufumi Sato
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K.T. wrote the text. J.W. and Y.S. reviewed and edited the manuscript before submission.

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Correspondence to Yasufumi Sato.

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Nature Reviews Nephrology thanks Abolfazl Zarjou and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Capillary rarefaction

A reduction in capillary vessel density.

Pericytes

Cells that enwrap capillaries and microvessels.

Vascular hyperpermeability

Excessive leakage of fluids and proteins from the blood vessel owing to an enhanced ability of the vessel walls to enable the passage of small molecules.

Intracapillary hyaline pseudothrombi

Intracapillary thrombi-like plugs that do not contain platelets and fibrin.

Occipital encephalocele

A defect in the back (occipital area) of the skull that results in a sac-like protrusion of the brain and meninges.

Chylous ascites

Retention of triglyceride-rich lymph in the peritoneal cavity.

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Tanabe, K., Wada, J. & Sato, Y. Targeting angiogenesis and lymphangiogenesis in kidney disease. Nat Rev Nephrol 16, 289–303 (2020). https://doi.org/10.1038/s41581-020-0260-2

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