Skip to content
2000
image of Type IV Collagen-Targeting Nanoparticles for Efficient Delivery to the Renal Interstitium in Fibrotic Kidneys

Abstract

Introduction

Renal fibrosis is recognized as the final common pathway of chronic kidney disease (CKD) progression, ultimately leading to end-stage renal failure and defined by excessive accumulation of extracellular matrix (ECM) by renal myofibroblasts in the interstitium. To establish an effective drug delivery system targeting fibrotic lesions, we developed nanoparticles modified with short-chain peptides that bind type IV collagen (Col IV), a distinct ECM component remodeled in fibrosis.

Methods

Col IV-targeting nanoparticles were intravenously administered to a unilateral ureteral obstruction (UUO) rat model of renal fibrosis. The distribution of these nanoparticles to the renal interstitium was examined via fluorescence-based ex vivo imaging and analysis of frozen kidney tissue sections. Additionally, we assessed cellular uptake in renal fibroblasts (NRK-49F), with or without transforming growth factor-beta 1 (TGF-β1) stimulation, using flow cytometry.

Results

Both Col IV-targeting and non-targeting nanoparticles exhibited increased distribution in the fibrotic renal interstitium compared to healthy tissue. Moreover, the Col IV-targeting nanoparticles localized more extensively in the fibrotic interstitium than their non-targeting counterparts. In vitro, Col IV-targeting nanoparticles also showed significantly higher accumulation in NRK-49F cells, irrespective of TGF-β1 stimulation, compared to non-targeting nanoparticles.

Discussion

In a UUO-induced renal fibrosis model, these nanoparticles efficiently migrated to the fibrotic renal interstitium, and in vitro experiments using NRK-49F cells demonstrated enhanced uptake by renal fibroblasts and myofibroblasts, central mediators of ECM deposition in fibrotic progression.

Conclusion

We successfully fabricated and evaluated Col IV-targeting nanoparticles, which may serve as an effective drug delivery platform for antifibrotic therapies, potentially mitigating CKD progression.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cdd/10.2174/0115672018377505250523040529
2025-05-26
2025-08-13

  • From This Site

    /content/journals/cdd/10.2174/0115672018377505250523040529
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Xing L. Chang X. Shen L. Zhang C. Fan Y. Cho C. Zhang Z. Jiang H. Progress in drug delivery system for fibrosis therapy. Asian J. Pharm. Sci. 2021 16 1 47 61 10.1016/j.ajps.2020.06.005 33613729
    [Google Scholar]
  2. Huang R. Fu P. Ma L. Kidney fibrosis: From mechanisms to therapeutic medicines. Signal Transduct. Target. Ther. 2023 8 1 129 10.1038/s41392‑023‑01379‑7 36932062
    [Google Scholar]
  3. Zhang Y.L. Tang T.T. Wang B. Wen Y. Feng Y. Yin Q. Jiang W. Zhang Y. Li Z.L. Wu M. Wu Q.L. Song J. Crowley S.D. Lan H.Y. Lv L.L. Liu B.C. Identification of a novel ECM remodeling macrophage subset in AKI to CKD transition by integrative spatial and single‐cell analysis. Adv. Sci. 2024 11 38 2309752 10.1002/advs.202309752 39119903
    [Google Scholar]
  4. Liu Y. Cellular and molecular mechanisms of renal fibrosis. Nat. Rev. Nephrol. 2011 7 12 684 696 10.1038/nrneph.2011.149 22009250
    [Google Scholar]
  5. Kalantar-Zadeh K. Jafar T.H. Nitsch D. Neuen B.L. Perkovic V. Chronic kidney disease. Lancet 2021 398 10302 786 802 10.1016/S0140‑6736(21)00519‑5 34175022
    [Google Scholar]
  6. Panizo S. Martínez-Arias L. Alonso-Montes C. Cannata P. Martín-Carro B. Fernández-Martín J.L. Naves-Díaz M. Carrillo-López N. Cannata-Andía J.B. Fibrosis in chronic kidney disease: Pathogenesis and consequences. Int. J. Mol. Sci. 2021 22 1 408 10.3390/ijms22010408 33401711
    [Google Scholar]
  7. Park S.A. Kim M.J. Park S.Y. Kim J.S. Lee S.J. Woo H.A. Kim D.K. Nam J.S. Sheen Y.Y. EW-7197 inhibits hepatic, renal, and pulmonary fibrosis by blocking TGF-β/Smad and ROS signaling. Cell. Mol. Life Sci. 2015 72 10 2023 2039 10.1007/s00018‑014‑1798‑6 25487606
    [Google Scholar]
  8. Li R. Guo Y. Zhang Y. Zhang X. Zhu L. Yan T. Salidroside ameliorates renal interstitial fibrosis by inhibiting the TLR4/NF-κB and MAPK signaling pathways. Int. J. Mol. Sci. 2019 20 5 1103 10.3390/ijms20051103 30836660
    [Google Scholar]
  9. Wang R. Wu G. Dai T. Lang Y. Chi Z. Yang S. Dong D. Naringin attenuates renal interstitial fibrosis by regulating the TGF‑β/Smad signaling pathway and inflammation. Exp. Ther. Med. 2020 21 1 66 10.3892/etm.2020.9498 33365066
    [Google Scholar]
  10. Wang Y. Ping Z. Gao H. Liu Z. Xv Q. Jiang X. Yu W. LYC inhibits the AKT signaling pathway to activate autophagy and ameliorate TGFB-induced renal fibrosis. Autophagy 2024 20 5 1114 1133 10.1080/15548627.2023.2287930 38037248
    [Google Scholar]
  11. Liang Z. Tang Z. Zhu C. Li F. Chen S. Han X. Zheng R. Hu X. Lin R. Pei Q. Yin C. Wang J. Tang C. Cao N. Zhao J. Wang R. Li X. Luo N. Wen Q. Yu J. Li J. Xia X. Zheng X. Wang X. Huang N. Zhong Z. Mo C. Chen P. Wang Y. Fan J. Guo Y. Zhong H. Liu J. Peng Z. Mao H. Shi G.P. Bonventre J.V. Chen W. Zhou Y. Intestinal CXCR6+ ILC3s migrate to the kidney and exacerbate renal fibrosis via IL-23 receptor signaling enhanced by PD-1 expression. Immunity 2024 57 6 1306 1323.e8 10.1016/j.immuni.2024.05.004 38815582
    [Google Scholar]
  12. Li J. Shu L. Jiang Q. Feng B. Bi Z. Zhu G. Zhang Y. Li X. Wu J. Oridonin ameliorates renal fibrosis in diabetic nephropathy by inhibiting the Wnt/β-catenin signaling pathway. Ren. Fail. 2024 46 1 2347462 10.1080/0886022X.2024.2347462 38832497
    [Google Scholar]
  13. Loboda A. Sobczak M. Jozkowicz A. Dulak J. TGF- β 1/Smads and miR-21 in renal fibrosis and inflammation. Mediators Inflamm. 2016 2016 1 12 10.1155/2016/8319283 27610006
    [Google Scholar]
  14. Liu Y. Bi X. Xiong J. Han W. Xiao T. Xu X. Yang K. Liu C. Jiang W. He T. Yu Y. Li Y. Zhang J. Zhang B. Zhao J. MicroRNA-34a promotes renal fibrosis by downregulation of klotho in tubular epithelial cells. Mol. Ther. 2019 27 5 1051 1065 10.1016/j.ymthe.2019.02.009 30853453
    [Google Scholar]
  15. Peng F. Gong W. Li S. Yin B. Zhao C. Liu W. Chen X. Luo C. Huang Q. Chen T. Sun L. Fang S. Zhou W. Li Z. Long H. circRNA_010383 Acts as a sponge for miR-135a, and its downregulated expression contributes to renal fibrosis in diabetic nephropathy. Diabetes 2021 70 2 603 615 10.2337/db20‑0203 33472945
    [Google Scholar]
  16. Zeisberg M. Kalluri R. Physiology of the renal interstitium. Clin. J. Am. Soc. Nephrol. 2015 10 10 1831 1840 10.2215/CJN.00640114 25813241
    [Google Scholar]
  17. Razzaque M.S. Koji T. Horita Y. Nishihara M. Harada T. Nakane P.K. Taguchi T. Synthesis of type III Collagen and type IV collagen by tubular epithelial cells in diabetic nephropathy. Pathol. Res. Pract. 1995 191 11 1099 1104 10.1016/S0344‑0338(11)80654‑0 8822111
    [Google Scholar]
  18. Huang X. Ma Y. Li Y. Han F. Lin W. Targeted drug delivery systems for kidney diseases. Front. Bioeng. Biotechnol. 2021 9 683247 10.3389/fbioe.2021.683247 34124026
    [Google Scholar]
  19. Hou Y. Zhu L. Ye X. Ke Q. Zhang Q. Xie X. Piao J. Wei Y. Integrated oral microgel system ameliorates renal fibrosis by hitchhiking co-delivery and targeted gut flora modulation. J. Nanobiotechnology 2024 22 1 305 10.1186/s12951‑024‑02586‑2 38822364
    [Google Scholar]
  20. Wang Y. He W. Ren P. Zhao L. Zheng D. Jin J. Carthamin yellow-loaded glycyrrhetinic acid liposomes alleviate interstitial fibrosis in diabetic nephropathy. Ren. Fail. 2025 47 1 2459356 10.1080/0886022X.2025.2459356 39904762
    [Google Scholar]
  21. He S. Li X. He Y. Guo L. Dong Y. Wang L. Yang L. Li L. Huang S. Fu J. Lin Q. Zhang Z. Zhang L. High-density lipoprotein nanoparticles spontaneously target to damaged renal tubules and alleviate renal fibrosis by remodeling the fibrotic niches. Nat. Commun. 2025 16 1 1061 10.1038/s41467‑025‑56223‑z 39870661
    [Google Scholar]
  22. Chan J.M. Zhang L. Tong R. Ghosh D. Gao W. Liao G. Yuet K.P. Gray D. Rhee J.W. Cheng J. Golomb G. Libby P. Langer R. Farokhzad O.C. Spatiotemporal controlled delivery of nanoparticles to injured vasculature. Proc. Natl. Acad. Sci. USA 2010 107 5 2213 2218 10.1073/pnas.0914585107 20133865
    [Google Scholar]
  23. Ishizawa K. Togami K. Tada H. Chono S. Multiscale live imaging using förster resonance energy transfer (FRET) for evaluating the biological behavior of nanoparticles as drug carriers. J. Pharm. Sci. 2020 109 12 3608 3616 10.1016/j.xphs.2020.08.028 32926888
    [Google Scholar]
  24. Ohno S. Terada N. Ohno N. Saitoh S. Saitoh Y. Fujii Y. Significance of ‘in vivo cryotechnique’ for morphofunctional analyses of living animal organs. J. Electron Microsc. 2010 59 5 395 408 10.1093/jmicro/dfq058 20667816
    [Google Scholar]
  25. Cosgrove D. Liu S. Collagen IV diseases: A focus on the glomerular basement membrane in Alport syndrome. Matrix Biol. 2017 57-58 45 54 10.1016/j.matbio.2016.08.005 27576055
    [Google Scholar]
  26. Au K.M. Hyder S.N. Wagner K. Shi C. Kim Y.S. Caster J.M. Tian X. Min Y. Wang A.Z. Direct observation of early-stage high-dose radiotherapy-induced vascular injury via basement membrane-targeting nanoparticles. Small 2015 11 48 6404 6410 10.1002/smll.201501902 26577747
    [Google Scholar]
  27. Mi Y. Yang F. Bloomquist C. Xia Y. Sun B. Qi Y. Wagner K. Montgomery S.A. Zhang T. Wang A.Z. Biologically targeted photo‐crosslinkable nanopatch to prevent postsurgical peritoneal adhesion. Adv. Sci. 2019 6 19 1900809 10.1002/advs.201900809 31592414
    [Google Scholar]
  28. Yi Y. Ma J. Jianrao L. Wang H. Zhao Y. WISP3 prevents fibroblast–myofibroblast transdifferentiation in NRK-49F cells. Biomed. Pharmacother. 2018 99 306 312 10.1016/j.biopha.2018.01.005 29353205
    [Google Scholar]
  29. Trinh-Minh T. Chen C.W. Tran Manh C. Li Y.N. Zhu H. Zhou X. Chakraborty D. Zhang Y. Rauber S. Dees C. Lin N.Y. Kah D. Gerum R. Bergmann C. Kreuter A. Reuter C. Groeber-Becker F. Eckes B. Distler O. Fabry B. Ramming A. Schambony A. Schett G. Distler J.H.W. Noncanonical WNT5A controls the activation of latent TGF-β to drive fibroblast activation and tissue fibrosis. J. Clin. Invest. 2024 134 10 e159884 10.1172/JCI159884 38747285
    [Google Scholar]
  30. Nørregaard R. Mutsaers H.A.M. Frøkiær J. Kwon T.H. Obstructive nephropathy and molecular pathophysiology of renal interstitial fibrosis. Physiol. Rev. 2023 103 4 2847 2892 10.1152/physrev.00027.2022 37440209
    [Google Scholar]
  31. Martínez-Klimova E. Aparicio-Trejo O.E. Tapia E. Pedraza-Chaverri J. Unilateral ureteral obstruction as a model to investigate fibrosis-attenuating treatments. Biomolecules 2019 9 4 141 10.3390/biom9040141 30965656
    [Google Scholar]
  32. Chevalier R.L. Forbes M.S. Thornhill B.A. Ureteral obstruction as a model of renal interstitial fibrosis and obstructive nephropathy. Kidney Int. 2009 75 11 1145 1152 10.1038/ki.2009.86 19340094
    [Google Scholar]
  33. Sakai N. Bain G. Furuichi K. Iwata Y. Nakamura M. Hara A. Kitajima S. Sagara A. Miyake T. Toyama T. Sato K. Nakagawa S. Shimizu M. Kaneko S. Wada T. The involvement of autotaxin in renal interstitial fibrosis through regulation of fibroblast functions and induction of vascular leakage. Sci. Rep. 2019 9 1 7414 10.1038/s41598‑019‑43576‑x 31092842
    [Google Scholar]
  34. Yamaguchi I. Tchao B.N. Burger M.L. Yamada M. Hyodo T. Giampietro C. Eddy A.A. Vascular endothelial cadherin modulates renal interstitial fibrosis. Nephron, Exp. Nephrol. 2012 120 1 e20 e31 10.1159/000332026 22126970
    [Google Scholar]
  35. Pluen A. Boucher Y. Ramanujan S. McKee T.D. Gohongi T. di Tomaso E. Brown E.B. Izumi Y. Campbell R.B. Berk D.A. Jain R.K. Role of tumor–host interactions in interstitial diffusion of macromolecules: Cranial vs. subcutaneous tumors. Proc. Natl. Acad. Sci. USA 2001 98 8 4628 4633 10.1073/pnas.081626898 11274375
    [Google Scholar]
  36. Goodman T.T. Olive P.L. Pun S.H. Increased nanoparticle penetration in collagenase-treated multicellular spheroids. Int. J. Nanomedicine 2007 2 2 265 274 [From NLM Medline.]. 17722554
    [Google Scholar]
  37. Cabral H. Makino J. Matsumoto Y. Mi P. Wu H. Nomoto T. Toh K. Yamada N. Higuchi Y. Konishi S. Kano M.R. Nishihara H. Miura Y. Nishiyama N. Kataoka K. Systemic targeting of Lymph node metastasis through the blood vascular system by using size-controlled nanocarriers. ACS Nano 2015 9 5 4957 4967 10.1021/nn5070259 25880444
    [Google Scholar]
  38. Shelton E.L. Yang H.C. Zhong J. Salzman M.M. Kon V. Renal lymphatic vessel dynamics. Am. J. Physiol. Renal Physiol. 2020 319 6 F1027 F1036 10.1152/ajprenal.00322.2020 33103446
    [Google Scholar]
  39. McCright J. Naiknavare R. Yarmovsky J. Maisel K. Targeting lymphatics for nanoparticle drug delivery. Front. Pharmacol. 2022 13 887402 10.3389/fphar.2022.887402 35721179
    [Google Scholar]
  40. Gustafson H.H. Holt-Casper D. Grainger D.W. Ghandehari H. Nanoparticle uptake: The phagocyte problem. Nano Today 2015 10 4 487 510 10.1016/j.nantod.2015.06.006 26640510
    [Google Scholar]
  41. Kjøller L. Engelholm L.H. Høyer-Hansen M. Danø K. Bugge T.H. Behrendt N. uPARAP/endo180 directs lysosomal delivery and degradation of collagen IV. Exp. Cell Res. 2004 293 1 106 116 10.1016/j.yexcr.2003.10.008 14729061
    [Google Scholar]
  42. Okamura D.M. Pasichnyk K. Lopez-Guisa J.M. Collins S. Hsu D.K. Liu F.T. Eddy A.A. Galectin-3 preserves renal tubules and modulates extracellular matrix remodeling in progressive fibrosis. Am. J. Physiol. Renal Physiol. 2011 300 1 F245 F253 10.1152/ajprenal.00326.2010 20962111
    [Google Scholar]
  43. Melander M.C. Jürgensen H.J. Madsen D.H. Engelholm L.H. Behrendt N. The collagen receptor uPARAP/Endo180 in tissue degradation and cancer (Review). Int. J. Oncol. 2015 47 4 1177 1188 10.3892/ijo.2015.3120 26316068
    [Google Scholar]
  44. Pittayapruek P. Meephansan J. Prapapan O. Komine M. Ohtsuki M. Role of matrix metalloproteinases in photoaging and photocarcinogenesis. Int. J. Mol. Sci. 2016 17 6 868 10.3390/ijms17060868 27271600
    [Google Scholar]
  45. Gucciardo F. Pirson S. Baudin L. Lebeau A. Noël A. uPARAP/Endo180: A multifaceted protein of mesenchymal cells. Cell. Mol. Life Sci. 2022 79 5 255 10.1007/s00018‑022‑04249‑7 35460056
    [Google Scholar]
  46. Inkinen K.A. Soots A.P. Krogerus L.A. Lautenschlager I.T. Ahonen J.P. Fibrosis and matrix metalloproteinases in rat renal allografts. Transpl. Int. 2005 18 5 506 512 10.1111/j.1432‑2277.2004.00053.x 15819797
    [Google Scholar]
  47. Yang M. Huang H. Li J. Huang W. Wang H. Connective tissue growth factor increases matrix metalloproteinase‐2 and suppresses tissue inhibitor of matrix metalloproteinase‐2 production by cultured renal interstitial fibroblasts. Wound Repair Regen. 2007 15 6 817 824 10.1111/j.1524‑475X.2007.00284.x 18028129
    [Google Scholar]
  48. Sun X. Liu Y. Li C. Wang X. Zhu R. Liu C. Liu H. Wang L. Ma R. Fu M. Zhang D. Li Y. Recent advances of curcumin in the prevention and treatment of renal fibrosis. BioMed Res. Int. 2017 2017 1 9 10.1155/2017/2418671 28546962
    [Google Scholar]
  49. Rayego-Mateos S. Valdivielso J.M. New therapeutic targets in chronic kidney disease progression and renal fibrosis. Expert Opin. Ther. Targets 2020 24 7 655 670 10.1080/14728222.2020.1762173 32338087
    [Google Scholar]
  50. Nastase M.V. Zeng-Brouwers J. Wygrecka M. Schaefer L. Targeting renal fibrosis: Mechanisms and drug delivery systems. Adv. Drug Deliv. Rev. 2018 129 295 307 10.1016/j.addr.2017.12.019 29288033
    [Google Scholar]
  51. Di X. Li Y. Wei J. Li T. Liao B. Targeting fibrosis: From molecular mechanisms to advanced therapies. Adv. Sci. 2025 12 3 2410416 10.1002/advs.202410416 39665319
    [Google Scholar]
  52. Yu Z. He W. Shi W. Sulforaphane (Sul) reduces renal interstitial fibrosis (RIF) by controlling the inflammation and TGF-β/Smad signaling pathway. Appl. Biol. Chem. 2024 67 1 8 10.1186/s13765‑024‑00858‑x
    [Google Scholar]
  53. Lee K.M. Hwang Y.J. Jung G.S. Alantolactone attenuates renal fibrosis via inhibition of transforming growth factor β/Smad3 signaling pathway. Diabetes Metab. J. 2024 48 1 72 82 10.4093/dmj.2022.0231 38173367
    [Google Scholar]
  54. Wang X. Gu Z. Huang Y. Wang J. Tang S. Yang X. Wang J. MicroRNA-668 alleviates renal fibrosis through PPARα/PGC-1α pathway. Eur. J. Med. Res. 2024 29 1 631 10.1186/s40001‑024‑02248‑x 39732711
    [Google Scholar]
  55. Qu G. Li X. Jin R. Guan D. Ji J. Li S. Shi H. Tong P. Gan W. Zhang A. MicroRNA‐26a alleviates tubulointerstitial fibrosis in diabetic kidney disease by targeting PAR4. J. Cell. Mol. Med. 2024 28 3 e18099 10.1111/jcmm.18099 38164021
    [Google Scholar]
  56. Dong J. Liu M. Bian Y. Zhang W. Yuan C. Wang D. Zhou Z. Li Y. Shi Y. MicroRNA-204-5p ameliorates renal injury via regulating Keap1/Nrf2 pathway in diabetic kidney disease. Diabetes Metab. Syndr. Obes. 2024 17 75 92 10.2147/DMSO.S441082 38196512
    [Google Scholar]
/content/journals/cdd/10.2174/0115672018377505250523040529
Loading
Type IV Collagen-Targeting Nanoparticles for Efficient Delivery to the Renal Interstitium in Fibrotic Kidneys
Bentham Science Publishers ; https://doi.org/10.2174/0115672018377505250523040529
/content/journals/cdd/10.2174/0115672018377505250523040529
/content/journals/cdd/10.2174/0115672018377505250523040529
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: type IV collagen ; kidney-targeting drug delivery system ; renal interstitium ; unilateral ureteral obstruction model ; Renal fibrosis ; renal fibroblast

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test