Abstract
Loss of normal kidney function affects more than 10% of the population and contributes to morbidity and mortality. Kidney diseases are currently treated with immunosuppressive agents, antihypertensives and diuretics with partial but limited success. Most kidney disease is characterized by breakdown of the glomerular filtration barrier (GFB). Specialized podocyte cells maintain the GFB, and structure–function experiments and studies of intercellular communication between the podocytes and other GFB cells, combined with advances from genetics and genomics, have laid the groundwork for a new generation of therapies that directly intervene at the GFB. These include inhibitors of apolipoprotein L1 (APOL1), short transient receptor potential channels (TRPCs), soluble fms-like tyrosine kinase 1 (sFLT1; also known as soluble vascular endothelial growth factor receptor 1), roundabout homologue 2 (ROBO2), endothelin receptor A, soluble urokinase plasminogen activator surface receptor (suPAR) and substrate intermediates for coenzyme Q10 (CoQ10). These molecular targets converge on two key components of GFB biology: mitochondrial function and the actin–myosin contractile machinery. This Review discusses therapies and developments focused on maintaining GFB integrity, and the emerging questions in this evolving field.
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References
Iseki, K., Ikemiya, Y., Iseki, C. & Takishita, S. Proteinuria and the risk of developing end-stage renal disease. Kidney Int. 63, 1468–1474 (2003).
Fuhrman, D. Y. et al. Albuminuria, proteinuria, and renal disease progression in children with CKD. Clin. J. Am. Soc. Nephrol. 12, 912–920 (2017).
Kolb, A. et al. A national registry study of patient and renal survival in adult nephrotic syndrome. Kidney Int. Rep. 6, 449–459 (2021).
Abbate, M., Zoja, C. & Remuzzi, G. How does proteinuria cause progressive renal damage? J. Am. Soc. Nephrol. 17, 2974–2984 (2006).
Mann, J. F. E. et al. Liraglutide and renal outcomes in type 2 diabetes. N. Engl. J. Med. 377, 839–848 (2017).
Wanner, C. et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N. Engl. J. Med. 375, 323–334 (2016).
Wang, X. X. et al. SGLT2 protein expression is increased in human diabetic nephropathy: SGLT2 protein inhibition decreases renal lipid accumulation, inflammation, and the development of nephropathy in diabetic mice. J. Biol. Chem. 292, 5335–5348 (2017).
Uthman, L. et al. Empagliflozin and dapagliflozin reduce ROS generation and restore NO bioavailability in tumor necrosis factor α-stimulated human coronary arterial endothelial cells. Cell. Physiol. Biochem. 53, 865–886 (2019).
Cherney, D. Z. I. et al. Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): a randomised, double-blind, crossover trial. Lancet Diabetes Endocrinol. 8, 582–593 (2020).
Levey, A. S. et al. Change in albuminuria and GFR as end points for clinical trials in early stages of CKD: a scientific workshop sponsored by the National Kidney Foundation in collaboration with the US Food and Drug Administration and European Medicines Agency. Am. J. Kidney Dis. 75, 84–104 (2020).
Haraldsson, B., Nyström, J. & Deen, W. M. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol. Rev. 88, 451–487 (2008).
Meyrier, A. Focal and segmental glomerulosclerosis: multiple pathways are involved. Semin. Nephrol. 31, 326–332 (2011).
Pozzi, A. et al. β1 integrin expression by podocytes is required to maintain glomerular structural integrity. Dev. Biol. 316, 288–301 (2008).
Faul, C., Asanuma, K., Yanagida-Asanuma, E., Kim, K. & Mundel, P. Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol. 17, 428–437 (2007).
Perico, L., Conti, S., Benigni, A. & Remuzzi, G. Podocyte-actin dynamics in health and disease. Nat. Rev. Nephrol. 12, 692–710 (2016).
Kestila, M. et al. Positionally cloned gene for a novel glomerular protein — nephrin — is mutated in congenital nephrotic syndrome. Mol. Cell 1, 575–582 (1998).
Boute, N. et al. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat. Genet. 24, 349–354 (2000); erratum 25, 125 (2000).
Grahammer, F. et al. A flexible, multilayered protein scaffold maintains the slit in between glomerular podocytes. JCI Insight 1, e86177 (2016).
Winn, M. P. et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 308, 1801–1804 (2005).
Reiser, J. et al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat. Genet. 37, 739–744 (2005).
Yao, J. et al. α-Actinin-4-mediated FSGS: an inherited kidney disease caused by an aggregated and rapidly degraded cytoskeletal protein. PLoS Biol. 2, e167 (2004).
Gigante, M. et al. CD2AP mutations are associated with sporadic nephrotic syndrome and focal segmental glomerulosclerosis (FSGS). Nephrol. Dial. Transpl. 24, 1858–1864 (2009).
Brown, E. J. et al. Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis. Nat. Genet. 42, 72–76 (2010).
Ronco, P. Proteinuria: is it all in the foot? J. Clin. Invest. 117, 2079–2082 (2007).
Campanholle, G., Ligresti, G., Gharib, S. A. & Duffield, J. S. Cellular mechanisms of tissue fibrosis. 3. Novel mechanisms of kidney fibrosis. Am. J. Physiol. Cell Physiol. 304, C591–C603 (2013).
Butt, L. et al. A molecular mechanism explaining albuminuria in kidney disease. Nat. Metab. 2, 461–474 (2020).
Sison, K. et al. Glomerular structure and function require paracrine, not autocrine, VEGF–VEGFR-2 signaling. J. Am. Soc. Nephrol. 21, 1691–1701 (2010).
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).
Ballermann, B. J. Contribution of the endothelium to the glomerular permselectivity barrier in health and disease. Nephron Physiol. 106, p19–p25 (2007).
Fogo, A. B. & Kon, V. The glomerulus — a view from the inside — the endothelial cell. Int. J. Biochem. Cell Biol. 42, 1388–1397 (2010).
Haraldsson, B. & Nystrom, J. The glomerular endothelium: new insights on function and structure. Curr. Opin. Nephrol. Hypertens. 21, 258–263 (2012).
Jeansson, M., Bjorck, K., Tenstad, O. & Haraldsson, B. Adriamycin alters glomerular endothelium to induce proteinuria. J. Am. Soc. Nephrol. 20, 114–122 (2009).
Singh, A. et al. High glucose causes dysfunction of the human glomerular endothelial glycocalyx. Am. J. Physiol. Ren. Physiol. 300, F40–F48 (2011).
Sun, Y. B. et al. Glomerular endothelial cell injury and damage precedes that of podocytes in adriamycin-induced nephropathy. PLoS ONE 8, e55027 (2013).
Caprioli, J. et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108, 1267–1279 (2006).
Zhao, H. J. et al. Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. J. Am. Soc. Nephrol. 17, 2664–2669 (2006).
Yuen, D. A. et al. eNOS deficiency predisposes podocytes to injury in diabetes. J. Am. Soc. Nephrol. 23, 1810–1823 (2012).
Satchell, S. C. & Tooke, J. E. What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium? Diabetologia 51, 714–725 (2008).
Lajer, M. et al. Plasma concentration of asymmetric dimethylarginine (ADMA) predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy. Diabetes Care 31, 747–752 (2008).
Hanai, K. et al. Asymmetric dimethylarginine is closely associated with the development and progression of nephropathy in patients with type 2 diabetes. Nephrol. Dial. Transpl. 24, 1884–1888 (2009).
Shibata, R. et al. Involvement of asymmetric dimethylarginine (ADMA) in tubulointerstitial ischaemia in the early phase of diabetic nephropathy. Nephrol. Dial. Transpl. 24, 1162–1169 (2009).
Dellamea, B. S., Pinto, L. C., Leitao, C. B., Santos, K. G. & Canani, L. H. Endothelial nitric oxide synthase gene polymorphisms and risk of diabetic nephropathy: a systematic review and meta-analysis. BMC Med. Genet. 15, 9 (2014).
Zanchi, A. et al. Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism. Kidney Int. 57, 405–413 (2000).
Wang, Y. et al. COL4A3 gene variants and diabetic kidney disease in MODY. Clin. J. Am. Soc. Nephrol. 13, 1162–1171 (2018).
Salem, R. M. et al. Genome-wide association study of diabetic kidney disease highlights biology involved in glomerular basement membrane collagen. J. Am. Soc. Nephrol. 30, 2000–2016 (2019).
Sadowski, C. E. et al. A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J. Am. Soc. Nephrol. 26, 1279–1289 (2015).
Groopman, E., Goldstein, D. & Gharavi, A. Diagnostic utility of exome sequencing for kidney disease. N. Engl. J. Med. 380, 2080–2081 (2019).
Mele, C. et al. MYO1E mutations and childhood familial focal segmental glomerulosclerosis. N. Engl. J. Med. 365, 295–306 (2011).
Schuler, M. H. et al. Miro1-mediated mitochondrial positioning shapes intracellular energy gradients required for cell migration. Mol. Biol. Cell 28, 2159–2169 (2017).
Tang, C. et al. Mitochondrial quality control in kidney injury and repair. Nat. Rev. Nephrol. 17, 299–318 (2020).
Daniel, R., Mengeta, A., Bilodeau, P. & Lee, J. M. Mitochondria tether to focal adhesions during cell migration and regulate their size. Preprint at bioRxiv https://doi.org/10.1101/827998 (2019).
Brinkkoetter, P. T. et al. Anaerobic glycolysis maintains the glomerular filtration barrier independent of mitochondrial metabolism and dynamics. Cell Rep. 27, 1551–1566.e5 (2019).
Baek, J. H. et al. Deletion of the mitochondrial complex-IV cofactor heme a:farnesyltransferase causes focal segmental glomerulosclerosis and interferon response. Am. J. Pathol. 188, 2745–2762 (2018).
Lowik, M. M., Hol, F. A., Steenbergen, E. J., Wetzels, J. F. & van den Heuvel, L. P. Mitochondrial tRNALeu(UUR) mutation in a patient with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis. Nephrol. Dial. Transpl. 20, 336–341 (2005).
Guery, B. et al. The spectrum of systemic involvement in adults presenting with renal lesion and mitochondrial tRNA(Leu) gene mutation. J. Am. Soc. Nephrol. 14, 2099–2108 (2003).
Casalena, G. et al. Mpv17 in mitochondria protects podocytes against mitochondrial dysfunction and apoptosis in vivo and in vitro. Am. J. Physiol. Ren. Physiol. 306, F1372–F1380 (2014).
Widmeier, E. et al. ADCK4 deficiency destabilizes the coenzyme Q complex, which is rescued by 2,4-dihydroxybenzoic acid treatment. J. Am. Soc. Nephrol. 31, 1191–1211 (2020).
Herlitz, L. C. et al. Tenofovir nephrotoxicity: acute tubular necrosis with distinctive clinical, pathological, and mitochondrial abnormalities. Kidney Int. 78, 1171–1177 (2010).
Ayanga, B. A. et al. Dynamin-related protein 1 deficiency improves mitochondrial fitness and protects against progression of diabetic nephropathy. J. Am. Soc. Nephrol. 27, 2733–2747 (2016).
Kawakami, T. et al. Deficient autophagy results in mitochondrial dysfunction and FSGS. J. Am. Soc. Nephrol. 26, 1040–1052 (2015).
Daehn, I. et al. Endothelial mitochondrial oxidative stress determines podocyte depletion in segmental glomerulosclerosis. J. Clin. Invest. 124, 1608–1621 (2014).
Qi, H. et al. Glomerular endothelial mitochondrial dysfunction is essential and characteristic of diabetic kidney disease susceptibility. Diabetes 66, 763–778 (2017).
Fu, J. et al. Comparison of glomerular and podocyte mRNA profiles in streptozotocin-induced diabetes. J. Am. Soc. Nephrol. 27, 1006–1014 (2016).
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).
Baigent, C. & Lennon, R. Should we increase GFR with bardoxolone in Alport syndrome? J. Am. Soc. Nephrol. 29, 357–359 (2018).
Dinkova-Kostova, A. T. & Abramov, A. Y. The emerging role of Nrf2 in mitochondrial function. Free Radic. Bio Med. 88, 179–188 (2015).
Scarpulla, R. C. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim. Biophys. Acta 1813, 1269–1278 (2011).
Gomez, I. G. et al. Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways. J. Clin. Invest. 125, 141–156 (2015).
Ducasa, G. M. et al. ATP-binding cassette A1 deficiency causes cardiolipin-driven mitochondrial dysfunction in podocytes. J. Clin. Invest. 129, 3387–3400 (2019).
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).
Ma, L. et al. APOL1 renal-risk variants induce mitochondrial dysfunction. J. Am. Soc. Nephrol. 28, 1093–1105 (2017).
Kopp, J. B. et al. MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat. Genet. 40, 1175–1184 (2008).
Genovese, G. et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329, 841–845 (2010).
Larsen, C. P., Beggs, M. L., Saeed, M. & Walker, P. D. Apolipoprotein L1 risk variants associate with systemic lupus erythematosus-associated collapsing glomerulopathy. J. Am. Soc. Nephrol. 24, 722–725 (2013).
Duran, C. E. et al. Prevalence of APOL1 risk variants in afro-descendant patients with chronic kidney disease in a Latin American country. Int. J. Nephrol. 2019, 7076326 (2019).
Riella, C. et al. APOL1-associated kidney disease in Brazil. Kidney Int. Rep. 4, 923–929 (2019).
Friedman, D. J., Kozlitina, J., Genovese, G., Jog, P. & Pollak, M. R. Population-based risk assessment of APOL1 on renal disease. J. Am. Soc. Nephrol. 22, 2098–2105 (2011).
Dummer, P. D. et al. APOL1 kidney disease risk variants: an evolving landscape. Semin. Nephrol. 35, 222–236 (2015).
Nichols, B. et al. Innate immunity pathways regulate the nephropathy gene apolipoprotein L1. Kidney Int. 87, 332–342 (2015).
Wu, H. et al. AKI and collapsing glomerulopathy associated with COVID-19 and APOL 1 high-risk genotype. J. Am. Soc. Nephrol. 31, 1688–1695 (2020).
Vanwalleghem, G. et al. Coupling of lysosomal and mitochondrial membrane permeabilization in trypanolysis by APOL1. Nat. Commun. 6, 8078 (2015).
Bruno, J., Pozzi, N., Oliva, J. & Edwards, J. C. Apolipoprotein L1 confers pH-switchable ion permeability to phospholipid vesicles. J. Biol. Chem. 292, 18344–18353 (2017).
Kruzel-Davila, E. et al. APOL1-mediated cell injury involves disruption of conserved trafficking processes. J. Am. Soc. Nephrol. 28, 1117–1130 (2017).
Bruggeman, L. A., O’Toole, J. F. & Sedor, J. R. APOL1 polymorphisms and kidney disease: loss-of-function or gain-of-function? Am. J. Physiol. Ren. Physiol. 316, F1–F8 (2019).
Lee, B. T. et al. The APOL1 genotype of African American kidney transplant recipients does not impact 5-year allograft survival. Am. J. Transplant. 12, 1924–1928 (2012).
Freedman, B. I. et al. APOL1 genotype and kidney transplantation outcomes from deceased African American donors. Transplantation 100, 194–202 (2016).
Beckerman, P. et al. Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice. Nat. Med. 23, 429–438 (2017).
Khatua, A. K. et al. Exon 4-encoded sequence is a major determinant of cytotoxicity of apolipoprotein L1. Am. J. Physiol. Cell Physiol. 309, C22–C37 (2015).
Chun, J. et al. Recruitment of APOL1 kidney disease risk variants to lipid droplets attenuates cell toxicity. Proc. Natl Acad. Sci. USA 116, 3712–3721 (2019).
Shah, S. S. et al. APOL1 kidney risk variants induce cell death via mitochondrial translocation and opening of the mitochondrial permeability transition pore. J. Am. Soc. Nephrol. 30, 2355–2368 (2019).
Olabisi, O. A. et al. APOL1 kidney disease risk variants cause cytotoxicity by depleting cellular potassium and inducing stress-activated protein kinases. Proc. Natl Acad. Sci. USA 113, 830–837 (2016).
Fu, Y. et al. APOL1-G1 in nephrocytes induces hypertrophy and accelerates cell death. J. Am. Soc. Nephrol. 28, 1106–1116 (2017).
Wen, H. et al. APOL1 risk variants cause podocytes injury through enhancing endoplasmic reticulum stress. Biosci. Rep. 38, BSR20171713 (2018).
Okamoto, K. et al. APOL1 risk allele RNA contributes to renal toxicity by activating protein kinase R. Commun. Biol. 1, 188 (2018).
Aghajan, M. et al. Antisense oligonucleotide treatment ameliorates IFN-γ-induced proteinuria in APOL1-transgenic mice. JCI Insight 4, e126124 (2019).
Liang, S. S. et al. Clinico-pathological characteristics and outcomes of patients with biopsy-proven hypertensive nephrosclerosis: a retrospective cohort study. BMC Nephrol. 17, 42 (2016).
Vanhollebeke, B. et al. Human Trypanosoma evansi infection linked to a lack of apolipoprotein L-I. N. Engl. J. Med. 355, 2752–2756 (2006).
Kormann, R. et al. Roles of APOL1 G1 and G2 variants in sickle cell disease patients: kidney is the main target. Br. J. Haematol. 179, 323–335 (2017).
Freedman, B. I. et al. End-stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis Rheumatol. 66, 390–396 (2014).
Quinzii, C. et al. A mutation in para-hydroxybenzoate-polyprenyl transferase (COQ2) causes primary coenzyme Q10 deficiency. Am. J. Hum. Genet. 78, 345–349 (2006).
Heeringa, S. F. et al. COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J. Clin. Invest. 121, 2013–2024 (2011).
Lopez, L. C. et al. Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations. Am. J. Hum. Genet. 79, 1125–1129 (2006).
Ashraf, S. et al. ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J. Clin. Invest. 123, 5179–5189 (2013).
Korkmaz, E. et al. ADCK4-associated glomerulopathy causes adolescence-onset FSGS. J. Am. Soc. Nephrol. 27, 63–68 (2016).
Widmeier, E. et al. Treatment with 2,4-dihydroxybenzoic acid prevents FSGS progression and renal fibrosis in podocyte-specific Coq6knockout mice. J. Am. Soc. Nephrol. 30, 393–405 (2019).
Stanczyk, M., Balasz-Chmielewska, I., Lipska-Zietkiewicz, B. & Tkaczyk, M. CoQ10-related sustained remission of proteinuria in a child with COQ6 glomerulopathy — a case report. Pediatr. Nephrol. 33, 2383–2387 (2018).
Feng, C. et al. Coenzyme Q10 supplementation therapy for 2 children with proteinuria renal disease and ADCK4 mutation: case reports and literature review. Medicine 96, e8880 (2017).
Pierrel, F. Impact of chemical analogs of 4-hydroxybenzoic acid on coenzyme Q biosynthesis: from inhibition to bypass of coenzyme Q deficiency. Front. Physiol. 8, 436 (2017).
Doimo, M. et al. Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Q10 deficiency. Biochim. Biophys. Acta 1842, 1–6 (2014).
Freyer, C. et al. Rescue of primary ubiquinone deficiency due to a novel COQ7 defect using 2,4-dihydroxybensoic acid. J. Med. Genet. 52, 779–783 (2015).
Sidhom, E. H. et al. Targeting a Braf/Mapk pathway rescues podocyte lipid peroxidation in CoQ deficiency kidney disease. J. Clin. Invest. 131, e141380 (2021).
Gee, H. Y. et al. ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling. J. Clin. Invest. 123, 3243–3253 (2013).
Akilesh, S. et al. Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis. J. Clin. Invest. 121, 4127–4137 (2011).
Subramanian, B. et al. Mice with mutant Inf2 show impaired podocyte and slit diaphragm integrity in response to protamine-induced kidney injury. Kidney Int. 90, 363–372 (2016).
Subramanian, B. et al. FSGS-causing INF2 mutation impairs cleaved INF2 N-fragment functions in podocytes. J. Am. Soc. Nephrol. 31, 374–391 (2020).
Schell, C. et al. ARP3 controls the podocyte architecture at the kidney filtration barrier. Dev. Cell 47, 741–357.e8 (2018).
Sever, S., Damke, H. & Schmid, S. L. Dynamin:GTP controls the formation of constricted coated pits, the rate limiting step in clathrin-mediated endocytosis. J. Cell Biol. 150, 1137–1148 (2000).
Gu, C. et al. Direct dynamin–actin interactions regulate the actin cytoskeleton. EMBO J. 29, 3593–3606 (2010).
Schiffer, M. et al. Pharmacological targeting of actin-dependent dynamin oligomerization ameliorates chronic kidney disease in diverse animal models. Nat. Med. 21, 601–609 (2015).
Hill, T. et al. Small molecule inhibitors of dynamin I GTPase activity: development of dimeric tyrphostins. J. Med. Chem. 48, 7781–7788 (2005).
Greka, A. & Mundel, P. Calcium regulates podocyte actin dynamics. Semin. Nephrol. 32, 319–326 (2012).
Riehle, M. et al. TRPC6 G757D loss-of-function mutation associates with FSGS. J. Am. Soc. Nephrol. 27, 2771–2783 (2016).
Chiluiza, D., Krishna, S., Schumacher, V. A. & Schlondorff, J. Gain-of-function mutations in transient receptor potential C6 (TRPC6) activate extracellular signal-regulated kinases 1/2 (ERK1/2). J. Biol. Chem. 288, 18407–18420 (2013).
Kuwahara, K. et al. TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling. J. Clin. Invest. 116, 3114–3126 (2006).
Schlondorff, J., Del Camino, D., Carrasquillo, R., Lacey, V. & Pollak, M. R. TRPC6 mutations associated with focal segmental glomerulosclerosis cause constitutive activation of NFAT-dependent transcription. Am. J. Physiol. Cell Physiol. 296, C558–C569 (2009).
Wang, Y. et al. Activation of NFAT signaling in podocytes causes glomerulosclerosis. J. Am. Soc. Nephrol. 21, 1657–1666 (2010).
Farmer, L. K. et al. TRPC6 binds to and activates calpain, independent of its channel activity, and regulates podocyte cytoskeleton, cell adhesion, and motility. J. Am. Soc. Nephrol. 30, 1910–1924 (2019).
Krall, P. et al. Podocyte-specific overexpression of wild type or mutant Trpc6 in mice is sufficient to cause glomerular disease. PLoS ONE 5, e12859 (2010).
Eckel, J. et al. TRPC6 enhances angiotensin II-induced albuminuria. J. Am. Soc. Nephrol. 22, 526–535 (2011).
Bai, Y. et al. Structural basis for pharmacological modulation of the TRPC6 channel. eLife 9, e53311 (2020).
Tian, D. Q. et al. Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels. Sci. Signal. 3, ra77 (2010).
Wang, X. X. et al. TRPC5 does not cause or aggravate glomerular disease. J. Am. Soc. Nephrol. 29, 409–415 (2018).
Schaldecker, T. et al. Inhibition of the TRPC5 ion channel protects the kidney filter. J. Clin. Invest. 123, 5298–5309 (2013).
Zhou, Y. et al. A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models. Science 358, 1332–1336 (2017).
Yu, H. et al. Rac1 activation in podocytes induces rapid foot process effacement and proteinuria. Mol. Cell Biol. 33, 4755–4764 (2013).
Wei, C. L. et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat. Med. 17, 952–960 (2011).
Wei, C. et al. uPAR isoform 2 forms a dimer and induces severe kidney disease in mice. J. Clin. Invest. 129, 1946–1959 (2019).
Tzima, E., del Pozo, M. A., Shattil, S. J., Chien, S. & Schwartz, M. A. Activation of integrins in endothelial cells by fluid shear stress mediates Rho-dependent cytoskeletal alignment. EMBO J. 20, 4639–4647 (2001).
Wei, C. et al. Circulating suPAR in two cohorts of primary FSGS. J. Am. Soc. Nephrol. 23, 2051–2059 (2012).
Hayek, S. S. et al. Soluble urokinase receptor and chronic kidney disease. N. Engl. J. Med. 373, 1916–1925 (2015).
Botha, S. et al. Soluble urokinase plasminogen activator receptor as a prognostic marker of all-cause and cardiovascular mortality in a black population. Int. J. Cardiol. 184, 631–636 (2015).
Bock, M. E., Price, H. E., Gallon, L. & Langman, C. B. Serum soluble urokinase-type plasminogen activator receptor levels and idiopathic FSGS in children: a single-center report. Clin. J. Am. Soc. Nephrol. 8, 1304–1311 (2013).
Franco Palacios, C. R. et al. Urine but not serum soluble urokinase receptor (suPAR) may identify cases of recurrent FSGS in kidney transplant candidates. Transplantation 96, 394–399 (2013).
Spinale, J. M. et al. A reassessment of soluble urokinase-type plasminogen activator receptor in glomerular disease. Kidney Int. 87, 564–574 (2015).
Walden Biosciences Launches. Walden Biosciences https://www.waldenbiosciences.com/walden-biosciences-launches-to-transform-the-treatment-of-kidney-disease/ (2020).
Wang, H. et al. Noninvasive assessment of antenatal hydronephrosis in mice reveals a critical role for Robo2 in maintaining anti-reflux mechanism. PLoS ONE 6, e24763 (2011).
Hwang, D. Y. et al. Mutations of the SLIT2–ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract. Hum. Genet. 134, 905–916 (2015).
Lu, W. N. et al. Disruption of ROBO2 is associated with urinary tract anomalies and confers risk of vesicoureteral reflux. Am. J. Kidney Dis. 49, A56–A56 (2007).
Fan, X. P. et al. Inhibitory effects of Robo2 on nephrin: a crosstalk between positive and negative signals regulating podocyte structure. Cell Rep. 2, 52–61 (2012).
Fan, X. P. et al. SLIT2/ROBO2 signaling pathway inhibits nonmuscle myosin IIA activity and destabilizes kidney podocyte adhesion. JCI Insight 1, e86934 (2016).
Kopp, J. B. Glomerular pathology in autosomal dominant MYH9 spectrum disorders: what are the clues telling us about disease mechanism? Kidney Int. 78, 130–133 (2010).
Johnstone, D. B. et al. Podocyte-specific deletion of Myh9 encoding nonmuscle myosin heavy chain 2A predisposes mice to glomerulopathy. Mol. Cell. Biol. 31, 2162–2170 (2011).
Pisarek-Horowitz, A. et al. Loss of roundabout guidance receptor 2 (Robo2) in podocytes protects adult mice from glomerular injury by maintaining podocyte foot process structure. Am. J. Pathol. 190, 799–816 (2020).
Sakurai, T., Yanagisawa, M. & Masaki, T. Molecular characterization of endothelin receptors. Trends Pharmacol. Sci. 13, 103–108 (1992).
Zeravica, R. et al. Plasma endothelin-1 levels and albuminuria in patients with type 2 diabetes mellitus. Med. Pregl. 69, 140–145 (2016).
Zanatta, C. M. et al. Endothelin-1 levels and albuminuria in patients with type 2 diabetes mellitus. Diabetes Res. Clin. Pract. 80, 299–304 (2008).
Chen, H. C. et al. Plasma and urinary endothelin-1 in focal segmental glomerulosclerosis. J. Clin. Lab. Anal. 15, 59–63 (2001).
Gupta, R. M. et al. A genetic variant associated with five vascular diseases is a distal regulator of endothelin-1 gene expression. Cell 170, 522–533.e15 (2017).
Rahman, T., Baker, M., Hall, D. H., Avery, P. J. & Keavney, B. Common genetic variation in the type A endothelin-1 receptor is associated with ambulatory blood pressure: a family study. J. Hum. Hypertens. 22, 282–288 (2008).
Sorensen, S. S., Madsen, J. K. & Pedersen, E. B. Systemic and renal effect of intravenous infusion of endothelin-1 in healthy human volunteers. Am. J. Physiol. 266, F411–F418 (1994).
Badr, K. F. et al. Mesangial cell, glomerular and renal vascular responses to endothelin in the rat kidney. Elucidation of signal transduction pathways. J. Clin. Invest. 83, 336–342 (1989).
Shin, S. J., Lee, Y. J. & Tsai, J. H. The correlation of plasma and urine endothelin-1 with the severity of nephropathy in Chinese patients with type 2 diabetes. Scand. J. Clin. Lab. Invest. 56, 571–576 (1996).
Collino, F. et al. Preeclamptic sera induce nephrin shedding from podocytes through endothelin-1 release by endothelial glomerular cells. Am. J. Physiol. Ren. Physiol. 294, F1185–F1194 (2008).
Saleh, M. A., Boesen, E. I., Pollock, J. S., Savin, V. J. & Pollock, D. M. Endothelin-1 increases glomerular permeability and inflammation independent of blood pressure in the rat. Hypertension 56, 942–949 (2010).
Miao, L., Dai, Y. & Zhang, J. Mechanism of RhoA/Rho kinase activation in endothelin-1-induced contraction in rabbit basilar artery. Am. J. Physiol. Heart Circ. Physiol. 283, H983–H989 (2002).
Clerk, A. et al. Regulation of mitogen-activated protein kinases in cardiac myocytes through the small G protein Rac1. Mol. Cell. Biol. 21, 1173–1184 (2001).
Morigi, M. et al. In response to protein load podocytes reorganize cytoskeleton and modulate endothelin-1 gene: implication for permselective dysfunction of chronic nephropathies. Am. J. Pathol. 166, 1309–1320 (2005).
Morigi, M. et al. Shigatoxin-induced endothelin-1 expression in cultured podocytes autocrinally mediates actin remodeling. Am. J. Pathol. 169, 1965–1975 (2006).
Barton, M. Therapeutic potential of endothelin receptor antagonists for chronic proteinuric renal disease in humans. Biochim. Biophys. Acta 1802, 1203–1213 (2010).
Barton, M. & Tharaux, P. L. Endothelin and the podocyte. Clin. Kidney J. 5, 17–27 (2012).
Lenoir, O. et al. Direct action of endothelin-1 on podocytes promotes diabetic glomerulosclerosis. J. Am. Soc. Nephrol. 25, 1050–1062 (2014).
Lee, T. M., Chung, T. H., Lin, S. Z. & Chang, N. C. Endothelin receptor blockade ameliorates renal injury by inhibition of RhoA/Rho-kinase signalling in deoxycorticosterone acetate-salt hypertensive rats. J. Hypertens. 32, 795–805 (2014).
Callera, G. E. & Bendhack, L. M. Mechanisms underlying the contractile response to endothelin-1 in the rat renal artery. Pharmacology 68, 131–139 (2003).
Nina A. Van de Lest, M. Z., Wolterbeek, R., Bruijn, J. A. & Scharpfenecker, M. Altered podocyte-endothelial cross-talk and increased oxidative stress in patients with FSGS [published abstract]. Kidney Week ASN TH-PO1059 (2019).
Boels, M. G. et al. Atrasentan reduces albuminuria by restoring the glomerular endothelial glycocalyx barrier in diabetic nephropathy. Diabetes 65, 2429–2439 (2016).
Garsen, M. et al. Endothelin-1 induces proteinuria by heparanase-mediated disruption of the glomerular glycocalyx. J. Am. Soc. Nephrol. 27, 3545–3551 (2016).
Barton, M. Endothelin antagonism and reversal of proteinuric renal disease in humans. Contrib. Nephrol. 172, 210–222 (2011).
Kohan, D. E. Endothelin, hypertension and chronic kidney disease: new insights. Curr. Opin. Nephrol. Hypertens. 19, 134–139 (2010).
Heerspink, H. J. L. et al. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet 393, 1937–1947 (2019).
Trachtman, H. et al. DUET: a phase 2 study evaluating the efficacy and safety of sparsentan in patients with FSGS. J. Am. Soc. Nephrol. 29, 2745–2754 (2018).
Calizo, R. C. et al. Disruption of podocyte cytoskeletal biomechanics by dasatinib leads to nephrotoxicity. Nat. Commun. 10, 2061 (2019).
Stillman, I. E. & Karumanchi, S. A. The glomerular injury of preeclampsia. J. Am. Soc. Nephrol. 18, 2281–2284 (2007).
Maynard, S. E. et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J. Clin. Invest. 111, 649–658 (2003).
Levine, R. J. et al. Circulating angiogenic factors and the risk of preeclampsia. N. Engl. J. Med. 350, 672–683 (2004).
Alon, T. et al. Vascular endothelial growth-factor acts as a survival factor for newly formed retinal-vessels and has implications for retinopathy of prematurity. Nat. Med. 1, 1024–1028 (1995).
Ferrara, N. Role of vascular endothelial growth factor in the regulation of angiogenesis. Kidney Int. 56, 794–814 (1999).
Muller-Deile, J. et al. Overexpression of preeclampsia induced microRNA-26a-5p leads to proteinuria in zebrafish. Sci. Rep. 8, 3621 (2018).
Eremina, V. et al. VEGF inhibition and renal thrombotic microangiopathy. N. Engl. J. Med. 358, 1129–1136 (2008).
Sugimoto, H. et al. Neutralization of circulating vascular endothelial growth factor (VEGF) by anti-VEGF antibodies and soluble VEGF receptor 1 (sFlt-1) induces proteinuria. J. Biol. Chem. 278, 12605–12608 (2003).
Matsubara, K., Higaki, T., Matsubara, Y. & Nawa, A. Nitric oxide and reactive oxygen species in the pathogenesis of preeclampsia. Int. J. Mol. Sci. 16, 4600–4614 (2015).
Venkatesha, S. et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat. Med. 12, 642–649 (2006).
Li, F. et al. eNOS deficiency acts through endothelin to aggravate sFlt-1-induced pre-eclampsia-like phenotype. J. Am. Soc. Nephrol. 23, 652–660 (2012).
Serrano, N. C. et al. Endothelial NO synthase genotype and risk of preeclampsia — a multicenter case–control study. Hypertension 44, 702–707 (2004).
Fatini, C. et al. Endothelial nitric oxide synthase gene influences the risk of pre-eclampsia, the recurrence of negative pregnancy events, and the maternal–fetal flow. J. Hypertens. 24, 1823–1829 (2006).
Weissgerber, T. L. et al. Early onset preeclampsia is associated with glycocalyx degradation and reduced microvascular perfusion. J. Am. Heart Assoc. 8, e010647 (2019).
Reitsma, S., Slaaf, D. W., Vink, H., van Zandvoort, M. A. & oude Egbrink, M. G. The endothelial glycocalyx: composition, functions, and visualization. Pflug. Arch. 454, 345–359 (2007).
Butler, M. J., Down, C. J., Foster, R. R. & Satchell, S. C. The pathological relevance of increased endothelial glycocalyx permeability. Am. J. Pathol. 190, 742–751 (2020).
Garovic, V. D. et al. Urinary podocyte excretion as a marker for preeclampsia. Am. J. Obstet. Gynecol. 196, 320–327 (2007).
Jin, J. et al. Soluble FLT1 binds lipid microdomains in podocytes to control cell morphology and glomerular barrier function. Cell 151, 384–399 (2012).
Bertuccio, C., Veron, D., Aggarwal, P. K., Holzman, L. & Tufro, A. Vascular endothelial growth factor receptor 2 direct interaction with nephrin links VEGF-A signals to actin in kidney podocytes. J. Biol. Chem. 286, 39933–39944 (2011).
Thadhani, R. et al. Removal of soluble fms-like tyrosine kinase-1 by dextran sulfate apheresis in preeclampsia. J. Am. Soc. Nephrol. 27, 903–913 (2016).
Thadhani, R. et al. Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia. Circulation 124, 940–950 (2011).
Khankin, E. V., Mandala, M., Colton, I., Karumanchi, S. A. & Osol, G. Hemodynamic, vascular, and reproductive impact of FMS-like tyrosine kinase 1 (FLT1) blockade on the uteroplacental circulation during normal mouse pregnancy. Biol. Reprod. 86, 57 (2012).
Turanov, A. A. et al. RNAi modulation of placental sFLT1 for the treatment of preeclampsia. Nat. Biotechnol. 36, 1164–1173 (2018).
Chadli, L. et al. Identification of regulators of the myofibroblast phenotype of primary dermal fibroblasts from early diffuse systemic sclerosis patients. Sci. Rep. 9, 4521 (2019).
Ebefors, K., Lassén, E., Anandakrishnan, N., Azeloglu, E. U. & Daehn, I. S. Modeling the glomerular filtration barrier and intercellular crosstalk. Front. Physiol. 12, 772 (2021).
Musah, S., Dimitrakakis, N., Camacho, D. M., Church, G. M. & Ingber, D. E. Directed differentiation of human induced pluripotent stem cells into mature kidney podocytes and establishment of a Glomerulus Chip. Nat. Protoc. 13, 1662–1685 (2018).
Musah, S. et al. Mature induced-pluripotent-stem-cell-derived human podocytes reconstitute kidney glomerular-capillary-wall function on a chip. Nat. Biomed. Eng. 1, 0069 (2017).
Petrosyan, A. et al. A glomerulus-on-a-chip to recapitulate the human glomerular filtration barrier. Nat. Commun. 10, 3656 (2019).
Dang, L. T. H. et al. Hyperactive FOXO1 results in lack of tip stalk identity and deficient microvascular regeneration during kidney injury. Biomaterials 141, 314–329 (2017).
Peltz, G. Can ‘humanized’ mice improve drug development in the 21st century? Trends Pharmacol. Sci. 34, 255–260 (2013).
de Ruyck, J., Brysbaert, G., Blossey, R. & Lensink, M. F. Molecular docking as a popular tool in drug design, an in silico travel. Adv. Appl. Bioinform. Chem. 9, 1–11 (2016).
Su, Q. et al. Structure of the human PKD1–PKD2 complex. Science 361, eaat9819 (2018).
Kuhlman, B. & Bradley, P. Advances in protein structure prediction and design. Nat. Rev. Mol. Cell Biol. 20, 681–697 (2019).
Goodnow, R. A., Dumelin, C. E. & Keefe, A. D. DNA-encoded chemistry: enabling the deeper sampling of chemical space. Nat. Rev. Drug Discov. 16, 131–147 (2017).
Lehmann, D. F., Eggleston, W. D. & Wang, D. Validation and clinical utility of the hERG IC50:Cmax ratio to determine the risk of drug-induced torsades de pointes: a meta-analysis. Pharmacotherapy 38, 341–348 (2018).
Weber, E. J. et al. Human kidney on a chip assessment of polymyxin antibiotic nephrotoxicity. JCI Insight 3, e123673 (2018).
Anzalone, A. V. et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 576, 149–157 (2019).
Porto, E. M., Komor, A. C., Slaymaker, I. M. & Yeo, G. W. Base editing: advances and therapeutic opportunities. Nat. Rev. Drug Discov. 19, 839–859 (2020).
Kottgen, A. et al. Multiple loci associated with indices of renal function and chronic kidney disease. Nat. Genet. 41, 712–717 (2009).
Pedigo, C. E. et al. Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury. J. Clin. Invest. 126, 3336–3350 (2016).
Komers, R. et al. Study design of the phase 3 sparsentan versus irbesartan (DUPLEX) study in patients with focal segmental glomerulosclerosis. Kidney Int. Rep. 5, 494–502 (2020).
Lassén, E. & Daehn, I. S. Molecular mechanismsin early diabetic kidney disease: glomerular endothelial cell dysfunction. Int. J. Mol. Sci. 21, 9456 (2020).
Dias, N. & Stein, C. A. Antisense oligonucleotides: basic concepts and mechanisms. Mol. Cancer Ther. 1, 347–355 (2002).
Hung, G. N. et al. Characterization of target mRNA reduction through in situ RNA hybridization in multiple organ systems following systemic antisense treatment in animals. Nucleic Acid Ther. 23, 369–378 (2013).
Engelhardt, J. A. Comparative renal toxicopathology of antisense oligonucleotides. Nucleic Acid Ther. 26, 199–209 (2016).
Crooke, S. T. et al. The effects of 2′-O-methoxyethyl oligonucleotides on renal function in humans. Nucleic Acid Ther. 28, 10–22 (2018).
Acknowledgements
I.S.D. is supported by National Institutes of Health (NIH) grant R01DK097253 and Department of Defense CDMRP grant E01 W81XWH2010836. Illustrations used during submission were created using BioRender.
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J.S.D. is a former employee of Vertex Pharmaceuticals, which is developing VX-147 for the treatment of APOL1-mediated kidney disease, holds Vertex stock and holds patents for the invention and use of Lademirsen for the treatment of kidney diseases including Alport syndrome. I.S.D. declares no competing interests.
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Daehn, I.S., Duffield, J.S. The glomerular filtration barrier: a structural target for novel kidney therapies. Nat Rev Drug Discov 20, 770–788 (2021). https://doi.org/10.1038/s41573-021-00242-0
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DOI: https://doi.org/10.1038/s41573-021-00242-0
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