Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=28337147
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
3D Proximal Tubule Tissues Recapitulate Key Aspects of Renal Physiology to Enable
Nephrotoxicity Testing
#MMPMID28337147
King SM
; Higgins JW
; Nino CR
; Smith TR
; Paffenroth EH
; Fairbairn CE
; Docuyanan A
; Shah VD
; Chen AE
; Presnell SC
; Nguyen DG
Front Physiol
2017[]; 8
(?): 123
PMID28337147
show ga
Due to its exposure to high concentrations of xenobiotics, the kidney proximal
tubule is a primary site of nephrotoxicity and resulting attrition in the drug
development pipeline. Current pre-clinical methods using 2D cell cultures and
animal models are unable to fully recapitulate clinical drug responses due to
limited in vitro functional lifespan, or species-specific differences. Using
Organovo's proprietary 3D bioprinting platform, we have developed a fully
cellular human in vitro model of the proximal tubule interstitial interface
comprising renal fibroblasts, endothelial cells, and primary human renal proximal
tubule epithelial cells to enable more accurate prediction of tissue-level
clinical outcomes. Histological characterization demonstrated formation of
extensive microvascular networks supported by endogenous extracellular matrix
deposition. The epithelial cells of the 3D proximal tubule tissues demonstrated
tight junction formation and expression of renal uptake and efflux transporters;
the polarized localization and function of P-gp and SGLT2 were confirmed.
Treatment of 3D proximal tubule tissues with the nephrotoxin cisplatin induced
loss of tissue viability and epithelial cells in a dose-dependent fashion, and
cimetidine rescued these effects, confirming the role of the OCT2 transporter in
cisplatin-induced nephrotoxicity. The tissues also demonstrated a fibrotic
response to TGF? as assessed by an increase in gene expression associated with
human fibrosis and histological verification of excess extracellular matrix
deposition. Together, these results suggest that the bioprinted 3D proximal
tubule model can serve as a test bed for the mechanistic assessment of human
nephrotoxicity and the development of pathogenic states involving
epithelial-interstitial interactions, making them an important adjunct to animal
studies.
free
free
free
