Human reconstructed kidney models

Abstract

The human kidney, which consists of up to 2 million nephrons, is critical for blood filtration, electrolyte balance, pH regulation, and fluid balance in the body. Animal experiments, particularly mice and rats, combined with advances in genetically modified technology have been the primary mechanism to study kidney injury in recent years. Mouse or rat kidneys, however, differ substantially from human kidneys at the anatomical, histological, and molecular levels. These differences combined with increased regulatory hurdles and shifting attitudes towards animal testing by non-specialists have led scientists to develop new and more relevant models of kidney injury. Although in vitro tissue culture studies are a valuable tool to study kidney injury and have yielded a great deal of insight, they are not a perfect model. Perhaps, the biggest limitation of tissue culture is that it cannot replicate the complex architecture, consisting of multiple cell types, of the kidney, and the interplay between these cells. Recent studies have found that pluripotent stem cells (PSCs), which are capable of differentiation into any cell type, can be used to generate kidney organoids. Organoids recapitulate the multicellular relationships and microenvironments of complex organs like kidney. Kidney organoids have been used to successfully model nephrotoxin-induced tubular and glomerular disease as well as complex diseases such as chronic kidney disease (CKD), which involves multiple cell types. In combination with genetic engineering techniques, such as CRISPR-Cas9, genetic diseases of the kidney can be reproduced in organoids. Thus, organoid models have the potential to predict drug toxicity and enhance drug discovery for human disease more accurately than animal models.

Functional Evaluation and Nephrotoxicity Assessment of Human Renal Proximal Tubule Cells on a Chip

“…Most published works on the PTOC frequently implement cell lines including human HK2 cells and porcine LLC-PK cells [ 29 ]. However, the deficient expression of cell–cell junctional proteins and essential transporters impeded these cells from generating tight barriers with strong transport functions [ 10 ]. To overcome these limitations, our PTOC model was established using hRPTECs, and achieved considerable improvement in cellular polarization, barrier integrity and active transporter expression against the HK2 model.…”

“…Conventionally, in vitro studies are performed in petri dishes or Transwell inserts, under static conditions. However, renal proximal tubular epithelial cells (RPTECs) in vivo are subjected to persistent luminal fluid shear stress (FSS) and inverse osmotic gradient across the epithelium, which is absent from these culture platforms [ 8 , 9 , 10 ]. To recapitulate such microenvironment features, a novel technology named organ-on-a-chip (OOC) is introduced [ 11 , 12 ].…”

Emerging Technologies to Study the Glomerular Filtration Barrier

“…While kidney organoids aim to comprehensively recreate all the renal compartments in vitro, the development of a kidney-on-a-chip system has focused on the in vitro generation of tubules and glomeruli. Successful development of PT structures has been confirmed by many groups (65,66). However, while tubular proteinuria (inability of tubules to reabsorb proteins) could be an interesting target for mechanistic as well as therapeutic studies ( 67), kidney tubules-on-a-chip have not been used to investigate these phenomena, its mechanisms of action or potential drug treatments.…”

Revolutionizing nephrology research: expanding horizons with kidney-on-a-chip and beyond

“…The data indicate that 10% of failure during both preclinical and clinical phases of drug development can be attributed to DIKI ( Cook et al, 2015 ). Traditional two-dimensional (2D) cell culture, lacking the physiological microenvironment, such as extracellular matrix (ECM) and fluid shear stress (FSS), fails to retain the indispensable in vivo characteristics of cells, rendering it an inadequate predictive model ( Kishi et al, 2021 ). OoC technology addresses this limitation by providing fluid flow, mechanical signals, and organ-level tissue interface, enabling the recreation of three-dimensional (3D) organ structures and physiological environments while facilitating dynamic observations of physiological or pathophysiological processes ( Wu et al, 2020 ).…”