Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Crosstalk between glomeruli and tubules

Nature Reviews Nephrology volume 21, pages 189–199 (2025)Cite this article

Subjects

Abstract

Models of kidney injury have classically concentrated on glomeruli as the primary site of injury leading to glomerulosclerosis or on tubules as the primary site of injury leading to tubulointerstitial fibrosis. However, current evidence on the mechanisms of progression of chronic kidney disease indicates that a complex interplay between glomeruli and tubules underlies progressive kidney injury. Primary glomerular injury can clearly lead to subsequent tubule injury. For example, damage to the glomerular filtration barrier can expose tubular cells to serum proteins, including complement and cytokines, that would not be present in physiological conditions and can promote the development of tubulointerstitial fibrosis and progressive decline in kidney function. In addition, although less well-studied, increasing evidence suggests that tubule injury, whether primary or secondary, can also promote glomerular damage. This feedback from the tubule to the glomerulus might be mediated by changes in the reabsorptive capacity of the tubule, which can affect the glomerular filtration rate, or by mediators released by injured proximal tubular cells that can induce damage in both podocytes and parietal epithelial cells. Examining the crosstalk between the various compartments of the kidney is important for understanding the mechanisms underlying kidney pathology and identifying potential therapeutic interventions.

Key points

  • Primary glomerular injury can lead to the development of subsequent tubule injury that promotes the development of tubulointerstitial fibrosis and a progressive decline in kidney function.

  • Serum factors — for example, immunoglobulins, complement proteins and lipids — rather than albumin itself seem to be key mediators of proximal tubule dysfunction associated with high proteinuria.

  • Increasing evidence suggests that injurious factors released from injured tubules, or loss of protective factors, can feedback to the glomerulus, where they promote or exacerbate glomerular injury.

  • In models of acute kidney injury, glomerulosclerosis is attenuated in atubular glomeruli. This effect might be related to reduced filtration in the atubular glomeruli and less oxidative stress in podocytes.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Potential mechanisms underlying filtered protein-induced proximal tubule damage.
Fig. 2: Long-chain fatty acids can promote damage in the proximal tubule.
Fig. 3: Potential mediators of tubule-induced glomerular injury.

Similar content being viewed by others

References

  1. Striker, G. E., Schainuck, L. I., Cutler, R. E. & Benditt, E. P. Structural-functional correlations in renal disease. I. A method for assaying and classifying histopathologic changes in renal disease. Hum. Pathol. 1, 615–630 (1970).

    CAS  PubMed  Google Scholar 

  2. Schainuck, L. I., Striker, G. E., Cutler, R. E. & Benditt, E. P. Structural-functional correlations in renal disease. II. The correlations. Hum. Pathol. 1, 631–641 (1970).

    CAS  PubMed  Google Scholar 

  3. Brenner, B. M., Goldszer, R. C. & Hostetter, T. H. Glomerular response to renal injury. Contrib. Nephrol. 33, 48–66 (1982).

    CAS  PubMed  Google Scholar 

  4. Ferenbach, D. A. & Bonventre, J. V. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat. Rev. Nephrol. 11, 264–276 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Basile, D. P. et al. Progression after AKI: understanding maladaptive repair processes to predict and identify therapeutic treatments. J. Am. Soc. Nephrol. 27, 687–697 (2016).

    CAS  PubMed  Google Scholar 

  6. Basile, D. P., Anderson, M. D. & Sutton, T. A. Pathophysiology of acute kidney injury. Compr. Physiol. 2, 1303–1353 (2012).

    PubMed  PubMed Central  Google Scholar 

  7. Harris, R. C., Seifter, J. L. & Brenner, B. M. Adaptation of Na+-H+ exchange in renal microvillus membrane vesicles. Role of dietary protein and uninephrectomy. J. Clin. Invest. 74, 1979–1987 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Liu, H. et al. Epigenomic and transcriptomic analyses define core cell types, genes and targetable mechanisms for kidney disease. Nat. Genet. 54, 950–962 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Qiu, C. et al. Renal compartment-specific genetic variation analyses identify new pathways in chronic kidney disease. Nat. Med. 24, 1721–1731 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Russo, L. M. et al. Impaired tubular uptake explains albuminuria in early diabetic nephropathy. J. Am. Soc. Nephrol. 20, 489–494 (2009).

    PubMed  PubMed Central  Google Scholar 

  11. Haymann, J. P. et al. Characterization and localization of the neonatal Fc receptor in adult human kidney. J. Am. Soc. Nephrol. 11, 632–639 (2000).

    CAS  PubMed  Google Scholar 

  12. Nielsen, R., Christensen, E. I. & Birn, H. Megalin and cubilin in proximal tubule protein reabsorption: from experimental models to human disease. Kidney Int. 89, 58–67 (2016).

    CAS  PubMed  Google Scholar 

  13. Park, C. H. & Maack, T. Albumin absorption and catabolism by isolated perfused proximal convoluted tubules of the rabbit. J. Clin. Invest. 73, 767–777 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Gudehithlu, K. P., Pegoraro, A. A., Dunea, G., Arruda, J. A. & Singh, A. K. Degradation of albumin by the renal proximal tubule cells and the subsequent fate of its fragments. Kidney Int. 65, 2113–2122 (2004).

    CAS  PubMed  Google Scholar 

  15. Molitoris, B. A. & Wagner, M. C. Is albumin toxic to the kidney: it depends? Clin. J. Am. Soc. Nephrol. 18, 1222–1224 (2023).

    PubMed  PubMed Central  Google Scholar 

  16. Bedin, M. et al. Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function. J. Clin. Invest. 130, 335–344 (2020).

    CAS  PubMed  Google Scholar 

  17. Molitoris, B. A., Sandoval, R. M., Yadav, S. P. S. & Wagner, M. C. Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications. Physiol. Rev. 102, 1625–1667 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Weyer, K. et al. Abolishment of proximal tubule albumin endocytosis does not affect plasma albumin during nephrotic syndrome in mice. Kidney Int. 93, 335–342 (2018).

    CAS  PubMed  Google Scholar 

  19. Birn, H., Nielsen, R. & Weyer, K. Tubular albumin uptake: is there evidence for a quantitatively important, receptor-independent mechanism? Kidney Int. 104, 1069–1073 (2023).

    CAS  PubMed  Google Scholar 

  20. Kantarci, S. et al. Mutations in LRP2, which encodes the multiligand receptor megalin, cause Donnai-Barrow and facio-oculo-acoustico-renal syndromes. Nat. Genet. 39, 957–959 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Charlton, J. R. et al. Beyond the tubule: pathological variants of LRP2, encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease. Am. J. Physiol. Renal Physiol. 319, F988–F999 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Faivre, A. et al. Spatiotemporal landscape of kidney tubular responses to glomerular proteinuria. J. Am. Soc. Nephrol. 35, 854–869 (2024).

    PubMed  Google Scholar 

  23. Langelueddecke, C. et al. Lipocalin-2 (24p3/neutrophil gelatinase-associated lipocalin (NGAL)) receptor is expressed in distal nephron and mediates protein endocytosis. J. Biol. Chem. 287, 159–169 (2012).

    CAS  PubMed  Google Scholar 

  24. Dizin, E. et al. Albuminuria induces a proinflammatory and profibrotic response in cortical collecting ducts via the 24p3 receptor. Am. J. Physiol. Renal Physiol. 305, F1053–F1063 (2013).

    CAS  PubMed  Google Scholar 

  25. Hinrichs, G. R. et al. Urokinase-type plasminogen activator contributes to amiloride-sensitive sodium retention in nephrotic range glomerular proteinuria in mice. Acta Physiol. 227, e13362 (2019).

    CAS  Google Scholar 

  26. Svenningsen, P. et al. Plasmin in nephrotic urine activates the epithelial sodium channel. J. Am. Soc. Nephrol. 20, 299–310 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Bohnert, B. N. et al. Urokinase-type plasminogen activator (uPA) is not essential for epithelial sodium channel (ENaC)-mediated sodium retention in experimental nephrotic syndrome. Acta Physiol. 227, e13286 (2019).

    CAS  Google Scholar 

  28. Staehr, M. et al. Aberrant glomerular filtration of urokinase-type plasminogen activator in nephrotic syndrome leads to amiloride-sensitive plasminogen activation in urine. Am. J. Physiol. Renal Physiol. 309, F235–F241 (2015).

    CAS  PubMed  Google Scholar 

  29. Xiao, M. et al. Plasminogen deficiency does not prevent sodium retention in a genetic mouse model of experimental nephrotic syndrome. Acta Physiol. 231, e13512 (2021).

    CAS  Google Scholar 

  30. Zoja, C., Benigni, A. & Remuzzi, G. Cellular responses to protein overload: key event in renal disease progression. Curr. Opin. Nephrol. Hypertens. 13, 31–37 (2004).

    CAS  PubMed  Google Scholar 

  31. Lidberg, K. A. et al. Serum protein exposure activates a core regulatory program driving human proximal tubule injury. J. Am. Soc. Nephrol. 33, 949–965 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Morais, C., Westhuyzen, J., Metharom, P. & Healy, H. High molecular weight plasma proteins induce apoptosis and Fas/FasL expression in human proximal tubular cells. Nephrol. Dial. Transpl. 20, 50–58 (2005).

    CAS  Google Scholar 

  33. Mackinnon, B. et al. Urinary transferrin, high molecular weight proteinuria and the progression of renal disease. Clin. Nephrol. 59, 252–258 (2003).

    CAS  PubMed  Google Scholar 

  34. Kalim, S. et al. Protein carbamylation and chronic kidney disease progression in the Chronic Renal Insufficiency Cohort Study. Nephrol. Dial. Transpl. 37, 139–147 (2021).

    Google Scholar 

  35. Noels, H. et al. Post-translational modifications in kidney diseases and associated cardiovascular risk. Nat. Rev. Nephrol. 20, 495–512 (2024).

    CAS  PubMed  Google Scholar 

  36. Yadav, S. P. S. et al. Mechanism of how carbamylation reduces albumin binding to FcRn contributing to increased vascular clearance. Am. J. Physiol. Renal Physiol. 320, F114–F129 (2021).

    CAS  PubMed  Google Scholar 

  37. Figueroa, S. M. et al. Oxidized albumin as a mediator of kidney disease. Antioxidants 10, 404 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Mishra, V. & Heath, R. J. Structural and biochemical features of human serum albumin essential for eukaryotic cell culture. Int. J. Mol. Sci. 22, 8411 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Afshinnia, F. et al. Increased lipogenesis and impaired β-oxidation predict type 2 diabetic kidney disease progression in American Indians. JCI Insight 4, e130317 (2019).

    PubMed  PubMed Central  Google Scholar 

  40. Arici, M., Chana, R., Lewington, A., Brown, J. & Brunskill, N. J. Stimulation of proximal tubular cell apoptosis by albumin-bound fatty acids mediated by peroxisome proliferator activated receptor-γ. J. Am. Soc. Nephrol. 14, 17–27 (2003).

    CAS  PubMed  Google Scholar 

  41. Kamijo, A. et al. Urinary free fatty acids bound to albumin aggravate tubulointerstitial damage. Kidney Int. 62, 1628–1637 (2002).

    CAS  PubMed  Google Scholar 

  42. Khan, S. et al. Kidney proximal tubule lipoapoptosis is regulated by fatty acid transporter-2 (FATP2). J. Am. Soc. Nephrol. 29, 81–91 (2018).

    CAS  PubMed  Google Scholar 

  43. Khan, S. et al. Lipotoxic disruption of NHE1 interaction with PI(4,5)P2 expedites proximal tubule apoptosis. J. Clin. Invest. 124, 1057–1068 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Mitrofanova, A., Merscher, S. & Fornoni, A. Kidney lipid dysmetabolism and lipid droplet accumulation in chronic kidney disease. Nat. Rev. Nephrol. 19, 629–645 (2023).

    CAS  PubMed  Google Scholar 

  45. Long, K. R., Rbaibi, Y., Gliozzi, M. L., Ren, Q. & Weisz, O. A. Differential kidney proximal tubule cell responses to protein overload by albumin and its ligands. Am. J. Physiol. Renal Physiol. 318, F851–F859 (2020).

    PubMed  PubMed Central  Google Scholar 

  46. Sun, H. et al. Nonesterified free fatty acids enhance the inflammatory response in renal tubules by inducing extracellular ATP release. Am. J. Physiol. Renal Physiol. 319, F292–F303 (2020).

    CAS  PubMed  Google Scholar 

  47. Khan, S. et al. Fatty acid transport protein-2 regulates glycemic control and diabetic kidney disease progression. JCI Insight 5, e136845 (2020).

    PubMed  PubMed Central  Google Scholar 

  48. Schelling, J. R. The contribution of lipotoxicity to diabetic kidney disease. Cells 11, 114465 (2022).

    Google Scholar 

  49. Chen, Y. et al. Involvement of FATP2-mediated tubular lipid metabolic reprogramming in renal fibrogenesis. Cell Death Dis. 11, 994 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Mori, Y. et al. KIM-1 mediates fatty acid uptake by renal tubular cells to promote progressive diabetic kidney disease. Cell Metab. 33, 1042–1061.e7 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Kon, V., Yang, H. C., Smith, L. E., Vickers, K. C. & Linton, M. F. High-density lipoproteins in kidney disease. Int. J. Mol. Sci. 22, 8201 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Morita, Y. et al. The role of complement in the pathogenesis of tubulointerstitial lesions in rat mesangial proliferative glomerulonephritis. J. Am. Soc. Nephrol. 8, 1363–1372 (1997).

    CAS  PubMed  Google Scholar 

  53. Nomura, A. et al. Role of complement in acute tubulointerstitial injury of rats with aminonucleoside nephrosis. Am. J. Pathol. 151, 539–547 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Nangaku, M., Pippin, J. & Couser, W. G. Complement membrane attack complex (C5b-9) mediates interstitial disease in experimental nephrotic syndrome. J. Am. Soc. Nephrol. 10, 2323–2331 (1999).

    CAS  PubMed  Google Scholar 

  55. Rangan, G. K., Pippin, J. W., Coombes, J. D. & Couser, W. G. C5b-9 does not mediate chronic tubulointerstitial disease in the absence of proteinuria. Kidney Int. 67, 492–503 (2005).

    CAS  PubMed  Google Scholar 

  56. Rangan, G. K. C5b-9 does not mediate tubulointerstitial injury in experimental acute glomerular disease characterized by selective proteinuria. World J. Nephrol. 5, 288–299 (2016).

    PubMed  PubMed Central  Google Scholar 

  57. Clark, E. C., Nath, K. A., Hostetter, M. K. & Hostetter, T. H. Role of ammonia in tubulointerstitial injury. Min. Electrolyte Metab. 16, 315–321 (1990).

    CAS  Google Scholar 

  58. Worn, M. et al. Proteasuria in nephrotic syndrome-quantification and proteomic profiling. J. Proteom. 230, 103981 (2021).

    Google Scholar 

  59. Branten, A. J., Kock-Jansen, M., Klasen, I. S. & Wetzels, J. F. Urinary excretion of complement C3d in patients with renal diseases. Eur. J. Clin. Invest. 33, 449–456 (2003).

    CAS  PubMed  Google Scholar 

  60. Timmerman, J. J. et al. Extrahepatic C6 is as effective as hepatic C6 in the generation of renal C5b-9 complexes. Kidney Int. 51, 1788–1796 (1997).

    CAS  PubMed  Google Scholar 

  61. Isaksson, G. L. et al. Urine excretion of C3dg and sC5b-9 coincide with proteinuria and development of preeclampsia in pregnant women with type-1 diabetes. J. Hypertens. 41, 223–232 (2023).

    CAS  PubMed  Google Scholar 

  62. Isaksson, G. L. et al. Proteinuria is accompanied by intratubular complement activation and apical membrane deposition of C3dg and C5b-9 in kidney transplant recipients. Am. J. Physiol. Renal Physiol. 322, F150–F163 (2022).

    CAS  PubMed  Google Scholar 

  63. Chen, S. J., Lv, L. L., Liu, B. C. & Tang, R. N. Crosstalk between tubular epithelial cells and glomerular endothelial cells in diabetic kidney disease. Cell Prolif. 53, e12763 (2020).

    PubMed  PubMed Central  Google Scholar 

  64. Munkonda, M. N. et al. Podocyte-derived microparticles promote proximal tubule fibrotic signaling via p38 MAPK and CD36. J. Extracell. Vesicles 7, 1432206 (2018).

    PubMed  PubMed Central  Google Scholar 

  65. Leung, J. C. K., Lai, K. N. & Tang, S. C. W. Role of mesangial-podocytic-tubular cross-talk in IgA nephropathy. Semin. Nephrol. 38, 485–495 (2018).

    CAS  PubMed  Google Scholar 

  66. Zhang, J. et al. Role of human mesangial-tubular crosstalk in secretory IgA-induced IgA nephropathy. Kidney Blood Press. Res. 46, 286–297 (2021).

    CAS  PubMed  Google Scholar 

  67. Jeon, J. S. et al. microRNA in extracellular vesicles released by damaged podocytes promote apoptosis of renal tubular epithelial cells. Cells 9, 1409 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Rana, R. et al. Glomerular-tubular crosstalk via cold shock Y-box binding protein-1 in the kidney. Kidney Int. 105, 65–83 (2024).

    CAS  PubMed  Google Scholar 

  69. Miao, Z. et al. Single cell regulatory landscape of the mouse kidney highlights cellular differentiation programs and disease targets. Nat. Commun. 12, 2277 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Muto, Y. et al. Single cell transcriptional and chromatin accessibility profiling redefine cellular heterogeneity in the adult human kidney. Nat. Commun. 12, 2190 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Nolin, A. C. et al. Proteinuria causes dysfunctional autophagy in the proximal tubule. Am. J. Physiol. Renal Physiol. 311, F1271–F1279 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Zhuang, Y. et al. Mitochondrial dysfunction confers albumin-induced NLRP3 inflammasome activation and renal tubular injury. Am. J. Physiol. Renal Physiol. 308, F857–F866 (2015).

    CAS  PubMed  Google Scholar 

  73. Doke, T. & Susztak, K. The multifaceted role of kidney tubule mitochondrial dysfunction in kidney disease development. Trends Cell Biol. 32, 841–853 (2022).

    PubMed  PubMed Central  Google Scholar 

  74. Abbate, M., Zoja, C. & Remuzzi, G. How does proteinuria cause progressive renal damage? J. Am. Soc. Nephrol. 17, 2974–2984 (2006).

    CAS  PubMed  Google Scholar 

  75. de Seigneux, S. et al. Proteinuria increases plasma phosphate by altering its tubular handling. J. Am. Soc. Nephrol. 26, 1608–1618 (2015).

    PubMed  Google Scholar 

  76. Hu, J. et al. Hypoxia inducible factor-1α mediates the profibrotic effect of albumin in renal tubular cells. Sci. Rep. 7, 15878 (2017).

    PubMed  PubMed Central  Google Scholar 

  77. Wilson, P. C. et al. Multimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression. Nat. Commun. 13, 5253 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Kirita, Y., Wu, H., Uchimura, K., Wilson, P. C. & Humphreys, B. D. Cell profiling of mouse acute kidney injury reveals conserved cellular responses to injury. Proc. Natl Acad. Sci. USA 117, 15874–15883 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Dhillon, P. et al. The nuclear receptor ESRRA protects from kidney disease by coupling metabolism and differentiation. Cell Metab. 33, 379–394.e8 (2021).

    CAS  PubMed  Google Scholar 

  80. Gerhardt, L. M. S., Liu, J., Koppitch, K., Cippa, P. E. & McMahon, A. P. Single-nuclear transcriptomics reveals diversity of proximal tubule cell states in a dynamic response to acute kidney injury. Proc. Natl Acad. Sci. USA 118, e2026684118 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Aggarwal, S. et al. SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys. Science 383, eadd6371 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Yang, L., Besschetnova, T. Y., Brooks, C. R., Shah, J. V. & Bonventre, J. V. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat. Med. 16, 535–543 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Taguchi, K. et al. Cyclin G1 induces maladaptive proximal tubule cell dedifferentiation and renal fibrosis through CDK5 activation. J. Clin. Invest 132, e158096 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Coca, S. G., Singanamala, S. & Parikh, C. R. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int. 81, 442–448 (2012).

    PubMed  Google Scholar 

  85. Chawla, L. S., Eggers, P. W., Star, R. A. & Kimmel, P. L. Acute kidney injury and chronic kidney disease as interconnected syndromes. N. Engl. J. Med. 371, 58–66 (2014).

    PubMed  PubMed Central  Google Scholar 

  86. Palant, C. E., Amdur, R. L. & Chawla, L. S. Long-term consequences of acute kidney injury in the perioperative setting. Curr. Opin. Anaesthesiol. 30, 100–104 (2017).

    CAS  PubMed  Google Scholar 

  87. Wang, J., Zhong, J., Yang, H. C. & Fogo, A. B. Cross talk from tubules to glomeruli. Toxicol. Pathol. 46, 944–948 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Jones, J. et al. Association of complete recovery from acute kidney injury with incident CKD stage 3 and all-cause mortality. Am. J. Kidney Dis. 60, 402–408 (2012).

    PubMed  PubMed Central  Google Scholar 

  89. Harris, R. C. & Zhang, M. Z. Cyclooxygenase metabolites in the kidney. Compr. Physiol. 1, 1729–1758 (2011).

    PubMed  Google Scholar 

  90. Capasso, G. A new cross-talk pathway between the renal tubule and its own glomerulus. Kidney Int. 71, 1087–1089 (2007).

    CAS  PubMed  Google Scholar 

  91. Sen, T. & Heerspink, H. J. L. A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors. Cell Metab. 33, 732–739 (2021).

    CAS  PubMed  Google Scholar 

  92. Tuttle, K. R. Digging deep into cells to find mechanisms of kidney protection by SGLT2 inhibitors. J. Clin. Invest. 133, e167700 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Nishiyama, A. & Kitada, K. Possible renoprotective mechanisms of SGLT2 inhibitors. Front. Med. 10, 1115413 (2023).

    Google Scholar 

  94. Billing, A. M. et al. Metabolic communication by SGLT2 inhibition. Circulation 149, 860–884 (2024).

    CAS  PubMed  Google Scholar 

  95. Albalawy, W. N. et al. SGLT2-independent effects of canagliflozin on NHE3 and mitochondrial complex I activity inhibit proximal tubule fluid transport and albumin uptake. Am. J. Physiol. Renal Physiol. 326, F1041–F1053 (2024).

    CAS  PubMed  Google Scholar 

  96. Zhang, Y., Thai, K., Kepecs, D. M. & Gilbert, R. E. Sodium-glucose linked cotransporter-2 inhibition does not attenuate disease progression in the rat remnant kidney model of chronic kidney disease. PLoS ONE 11, e0144640 (2016).

    PubMed  PubMed Central  Google Scholar 

  97. Zhu, Z. et al. Finerenone added to RAS/SGLT2 blockade for CKD in Alport syndrome. results of a randomized controlled trial with Col4a3-/- Mice. J. Am. Soc. Nephrol. 34, 1513–1520 (2023).

    PubMed  PubMed Central  Google Scholar 

  98. Schaub, J. A. et al. SGLT2 inhibitors mitigate kidney tubular metabolic and mTORC1 perturbations in youth-onset type 2 diabetes. J. Clin. Invest. 133, e164486 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Inoki, K. et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J. Clin. Invest. 121, 2181–2196 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Godel, M. et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J. Clin. Invest. 121, 2197–2209 (2011).

    PubMed  PubMed Central  Google Scholar 

  101. Packer, M. Critical reanalysis of the mechanisms underlying the cardiorenal benefits of SGLT2 inhibitors and reaffirmation of the nutrient deprivation signaling/autophagy hypothesis. Circulation 146, 1383–1405 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Haase, V. H. Regulation of erythropoiesis by hypoxia-inducible factors. Blood Rev. 27, 41–53 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Grgic, I. et al. Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis. Kidney Int. 82, 172–183 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Gao, L. et al. Restoration of E-cadherin by PPBICA protects against cisplatin-induced acute kidney injury by attenuating inflammation and programmed cell death. Lab. Invest. 98, 911–923 (2018).

    CAS  PubMed  Google Scholar 

  105. Xiong, C. et al. Pharmacological inhibition of Src kinase protects against acute kidney injury in a murine model of renal ischemia/reperfusion. Oncotarget 8, 31238–31253 (2017).

    PubMed  PubMed Central  Google Scholar 

  106. Tan, R. J. et al. Tubular injury triggers podocyte dysfunction by β-catenin-driven release of MMP-7. JCI Insight 4, e122399 (2019).

    PubMed  PubMed Central  Google Scholar 

  107. Ma, Y. et al. Paracrine effects of renal proximal tubular epithelial cells on podocyte injury under hypoxic conditions are mediated by arginase-II and TGF-β1. Int J. Mol. Sci. 24, 3587 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Lim, B. J. et al. Tubulointerstitial fibrosis can sensitize the kidney to subsequent glomerular injury. Kidney Int. 92, 1395–1403 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Zou, J. et al. Stabilization of hypoxia-inducible factor ameliorates glomerular injury sensitization after tubulointerstitial injury. Kidney Int. 99, 620–631 (2021).

    CAS  PubMed  Google Scholar 

  110. Xu, C. et al. Renal tubular Bim mediates the tubule-podocyte crosstalk via NFAT2 to induce podocyte cytoskeletal dysfunction. Theranostics 10, 6806–6824 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Han, X. et al. Targeting Sirtuin1 to treat aging-related tissue fibrosis: from prevention to therapy. Pharmacol. Ther. 229, 107983 (2022).

    CAS  PubMed  Google Scholar 

  112. Hasegawa, K. et al. Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes. Nat. Med. 19, 1496–1504 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Hasegawa, K. et al. Communication from tubular epithelial cells to podocytes through sirt1 and nicotinic acid metabolism. Curr. Hypertens. Rev. 12, 95–104 (2016).

    CAS  PubMed  Google Scholar 

  114. Yasuda, I. et al. Pre-emptive short-term nicotinamide mononucleotide treatment in a mouse model of diabetic nephropathy. J. Am. Soc. Nephrol. 32, 1355–1370 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Jones, B. A. et al. Nicotinamide riboside activates renal metabolism and protects the kidney in a model of Alport syndrome. Preprint at bioRxiv https://doi.org/10.1101/2024.02.26.580911 (2024).

  116. Bonventre, J. V. Primary proximal tubule injury leads to epithelial cell cycle arrest, fibrosis, vascular rarefaction, and glomerulosclerosis. Kidney Int. Suppl. 4, 39–44 (2014).

    CAS  Google Scholar 

  117. Lasagni, L. & Romagnani, P. Glomerular epithelial stem cells: the good, the bad, and the ugly. J. Am. Soc. Nephrol. 21, 1612–1619 (2010).

    PubMed  Google Scholar 

  118. Smeets, B. et al. Parietal epithelial cells participate in the formation of sclerotic lesions in focal segmental glomerulosclerosis. J. Am. Soc. Nephrol. 22, 1262–1274 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Kaverina, N. V. et al. Dual lineage tracing shows that glomerular parietal epithelial cells can transdifferentiate toward the adult podocyte fate. Kidney Int. 96, 597–611 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Shankland, S. J., Pippin, J. W. & Duffield, J. S. Progenitor cells and podocyte regeneration. Semin. Nephrol. 34, 418–428 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Kuppe, C. et al. Novel parietal epithelial cell subpopulations contribute to focal segmental glomerulosclerosis and glomerular tip lesions. Kidney Int. 96, 80–93 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Appel, D. et al. Recruitment of podocytes from glomerular parietal epithelial cells. J. Am. Soc. Nephrol. 20, 333–343 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Berger, K. & Moeller, M. J. Mechanisms of epithelial repair and regeneration after acute kidney injury. Semin. Nephrol. 34, 394–403 (2014).

    CAS  PubMed  Google Scholar 

  124. Angelotti, M. L. et al. Characterization of renal progenitors committed toward tubular lineage and their regenerative potential in renal tubular injury. Stem Cell 30, 1714–1725 (2012).

    CAS  Google Scholar 

  125. Ronconi, E. et al. Regeneration of glomerular podocytes by human renal progenitors. J. Am. Soc. Nephrol. 20, 322–332 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Schulte, K. et al. Origin of parietal podocytes in atubular glomeruli mapped by lineage tracing. J. Am. Soc. Nephrol. 25, 129–141 (2014).

    CAS  PubMed  Google Scholar 

  127. Pippin, J. W. et al. Cells of renin lineage are progenitors of podocytes and parietal epithelial cells in experimental glomerular disease. Am. J. Pathol. 183, 542–557 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Kaverina, N. V. et al. Tracking the stochastic fate of cells of the renin lineage after podocyte depletion using multicolor reporters and intravital imaging. PLoS ONE 12, e0173891 (2017).

    PubMed  PubMed Central  Google Scholar 

  129. Martinez, M. F. et al. Super-enhancers maintain renin-expressing cell identity and memory to preserve multi-system homeostasis. J. Clin. Invest. 128, 4787–4803 (2018).

    PubMed  PubMed Central  Google Scholar 

  130. Risdon, R. A., Sloper, J. C. & De Wardener, H. E. Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis. Lancet 2, 363–366 (1968).

    CAS  PubMed  Google Scholar 

  131. Welch, W. J., Baumgartl, H., Lubbers, D. & Wilcox, C. S. Nephron pO2 and renal oxygen usage in the hypertensive rat kidney. Kidney Int. 59, 230–237 (2001).

    CAS  PubMed  Google Scholar 

  132. Rosenberger, C., Rosen, S., Paliege, A. & Heyman, S. N. Pimonidazole adduct immunohistochemistry in the rat kidney: detection of tissue hypoxia. Methods Mol. Biol. 466, 161–174 (2009).

    CAS  PubMed  Google Scholar 

  133. Palm, F. & Nordquist, L. Renal oxidative stress, oxygenation, and hypertension. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R1229–R1241 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Fine, L. G., Orphanides, C. & Norman, J. T. Progressive renal disease: the chronic hypoxia hypothesis. Kidney Int. Suppl. 65, S74–S78 (1998).

    CAS  PubMed  Google Scholar 

  135. Manotham, K. et al. Transdifferentiation of cultured tubular cells induced by hypoxia. Kidney Int. 65, 871–880 (2004).

    PubMed  Google Scholar 

  136. Mimura, I. & Nangaku, M. The suffocating kidney: tubulointerstitial hypoxia in end-stage renal disease. Nat. Rev. Nephrol. 6, 667–678 (2010).

    CAS  PubMed  Google Scholar 

  137. Haase, V. H. Hypoxia-inducible factors in the kidney. Am. J. Physiol. Renal Physiol. 291, F271–F281 (2006).

    CAS  PubMed  Google Scholar 

  138. Haase, V. H. Pathophysiological consequences of HIF activation: HIF as a modulator of fibrosis. Ann. N. Y. Acad. Sci. 1177, 57–65 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Sugahara, M., Tanaka, T. & Nangaku, M. Hypoxia-inducible factor and oxygen biology in the kidney. Kidney360 1, 1021–1031 (2020).

    PubMed  PubMed Central  Google Scholar 

  140. Kaelin, W. G. Jr. & Ratcliffe, P. J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402 (2008).

    CAS  PubMed  Google Scholar 

  141. Nordquist, L. et al. Activation of hypoxia-inducible factors prevents diabetic nephropathy. J. Am. Soc. Nephrol. 26, 328–338 (2015).

    PubMed  Google Scholar 

  142. Bernhardt, W. M. et al. Involvement of hypoxia-inducible transcription factors in polycystic kidney disease. Am. J. Pathol. 170, 830–842 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Higgins, D. F. et al. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J. Clin. Invest. 117, 3810–3820 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Higgins, D. F., Kimura, K., Iwano, M. & Haase, V. H. Hypoxia-inducible factor signaling in the development of tissue fibrosis. Cell Cycle 7, 1128–1132 (2008).

    CAS  PubMed  Google Scholar 

  145. Rosenberger, C. et al. Immunohistochemical detection of hypoxia-inducible factor-1α in human renal allograft biopsies. J. Am. Soc. Nephrol. 18, 343–351 (2007).

    CAS  PubMed  Google Scholar 

  146. Li, Z. et al. Chromatin-accessibility estimation from single-cell ATAC-seq data with scOpen. Nat. Commun. 12, 6386 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Zhang, Y. et al. Endothelial progenitor cells-derived exosomal microRNA-21-5p alleviates sepsis-induced acute kidney injury by inhibiting RUNX1 expression. Cell Death Dis. 12, 335 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Chen, Q., Guan, X., Zuo, X., Wang, J. & Yin, W. The role of high mobility group box 1 (HMGB1) in the pathogenesis of kidney diseases. Acta Pharm. Sin. B 6, 183–188 (2016).

    PubMed  PubMed Central  Google Scholar 

  149. Grigoryev, D. N. et al. The local and systemic inflammatory transcriptome after acute kidney injury. J. Am. Soc. Nephrol. 19, 547–558 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Lie, M. L. et al. Lung T lymphocyte trafficking and activation during ischemic acute kidney injury. J. Immunol. 189, 2843–2851 (2012).

    CAS  PubMed  Google Scholar 

  151. Ba Aqeel, S. H., Sanchez, A. & Batlle, D. Angiotensinogen as a biomarker of acute kidney injury. Clin. Kidney J. 10, 759–768 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Marcussen, N. Atubular glomeruli in cisplatin-induced chronic interstitial nephropathy. An experimental stereological investigation. APMIS 98, 1087–1097 (1990).

    CAS  PubMed  Google Scholar 

  153. Marcussen, N. & Olsen, T. S. Atubular glomeruli in patients with chronic pyelonephritis. Lab. Invest. 62, 467–473 (1990).

    CAS  PubMed  Google Scholar 

  154. Najafian, B., Kim, Y., Crosson, J. T. & Mauer, M. Atubular glomeruli and glomerulotubular junction abnormalities in diabetic nephropathy. J. Am. Soc. Nephrol. 14, 908–917 (2003).

    PubMed  Google Scholar 

  155. Forbes, M. S., Thornhill, B. A. & Chevalier, R. L. Proximal tubular injury and rapid formation of atubular glomeruli in mice with unilateral ureteral obstruction: a new look at an old model. Am. J. Physiol. Renal Physiol. 301, F110–F117 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Gandhi, M., Olson, J. L. & Meyer, T. W. Contribution of tubular injury to loss of remnant kidney function. Kidney Int. 54, 1157–1165 (1998).

    CAS  PubMed  Google Scholar 

  157. Tanner, G. A., Gretz, N., Connors, B. A., Evan, A. P. & Steinhausen, M. Role of obstruction in autosomal dominant polycystic kidney disease in rats. Kidney Int. 50, 873–886 (1996).

    CAS  PubMed  Google Scholar 

  158. Yang, H. C. et al. Spatial transcriptomic analysis reveals altered gene expression in glomerular parietal epithelial cells following tubular injury. ASN Kidney Week 34, 315 (2023).

    Google Scholar 

Download references

Acknowledgements

These studies were supported by NIH grants DK51265, DK95785, DK62794 (R.C.H.), the VA Merit Award 00507969 (R.C.H.), the NIH grant DK56942 (A.F.) and The Vanderbilt Center for Kidney Disease.

Author information

Authors and Affiliations

  1. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA

    Agnes B. Fogo

  2. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Agnes B. Fogo & Raymond C. Harris

  3. Tennessee Department of Veterans Affairs, Nashville, TN, USA

    Raymond C. Harris

Authors
  1. Agnes B. Fogo
    View author publications

    Search author on:PubMed Google Scholar

  2. Raymond C. Harris
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Raymond C. Harris.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

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

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fogo, A.B., Harris, R.C. Crosstalk between glomeruli and tubules. Nat Rev Nephrol 21, 189–199 (2025). https://doi.org/10.1038/s41581-024-00907-0

Download citation

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41581-024-00907-0

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing