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Introduction to renal biology

The kidney is a key organ of the urinary system, which plays a pivotal role in many physiological processes such as the maintenance of homeostasis, the excretion of nitrogen waste and the secretion of endocrine factors.  Nephron -- the structural and functional unit of kidney -- is a highly complex organ comprised of convoluted tubules, the cortical collecting ducts, the calyxes, and the renal pelvis.  The epithelial cells located in the tubules and ducts differ in their physiology and morphology and exert critical functions in the kidney.

Renal cells in the proximal tubule play physiological roles in the re-absorption of small molecular weight proteins, peptides and glucose via receptors present on the villi of their luminal surface. This localization and biological role exposes these cells to numerous challenging stimuli in the event of any up-stream pathology, with excessive protein, glucose, toxins, advanced glycation end products (AGEs) and bacterial products all being able to perturb normal renal epithelial cell physiology. 

In vitro renal epithelial cell culture systems are considered to be the most valuable tool for studying renal physiology, nephrotoxicity studies, drug transporter studies, disease models, renal transplantation models, cancer models and more. Refer to our select references  highlighting different applications of Lonza's renal cells including but not limited to ADME-Tox research.

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Renal cells in the proximal tubule (RPTEC)

These cells come from the proximal tubule, the portion of the duct system of the nephron which leads from Bowman's capsule to the loop of Henle. They are involved in the re-absorption of small molecules through the microvilli of their luminal surface.

Renal cortical cells (HRCE) 
 

Heterogeneous mixture of epithelial cells from the cortex of the kidney. The population will include RPTEC and distal tubule epithelial cells. These cells are utilized to study important physiological processes like osmoregulation and excretion.  
 

Renal epithelial cells (HRE) 
 

These cells are isolated from the whole kidney and comprise of any epithelial cells including proximal tubule, distal tubule and glomerular cells. Kidneys have a very complex structure and contain diverse epithelia, e.g. in the convoluted tubules and the cortical ducts.

Renal drug transporters and nephrotoxicity

Renal transporters are promising tools that provide models to study the absorption, metabolism, elimination, (ADME) and toxicity properties of the compounds. The kidney is a vital organ for the elimination of therapeutic drugs and their metabolites. Renal drug transporters play an important role in tubular secretion and reabsorption of drug molecules in the kidney. Renal clearance is a major pathway of drug elimination that involves a variety of transporters predominantly expressed in the proximal tubule. These transporters work in tandem to eliminate drugs from the blood circulation into the urine. Numerous studies have suggested that transporters play a part in vivo in drug disposition, therapeutic efficacy and adverse drug reactions. Major clinically relevant renal transporters include P-gp, BCRP, organic cation transporter 2 (hOCT2) and organic anion transporters 1 (hOAT1) and 3 (hOAT3). Transporter-mediated drug–drug interactions (DDIs) are increasingly recognized as an important modifier of the pharmacokinetics and pharmacodynamics of drugs primarily to assess safety and efficacy profile of the substrate when consumed in conjunction with other drugs. One such study was done using Lonza’s Human Renal Proximal Tubule Epithelial Cells, where the effect of Cobicistat (COBI) on the cytotoxicity of Tenofovir (TFV) in renal cell cultures was examined to elucidate renal drug-drug interaction between these two components.

Nephrotoxicity resulting from drug exposure contributes to 19-25% of all cases of acute kidney injury. Exposure to drugs and chemicals often results in toxicity to living organisms.  Kidneys may be much more susceptible than other organs to the toxic effects of a variety of chemicals. Certain classes of drugs are known to cause renal failure by preferential accumulation within the proximal tubule cells. In vitro studies have been conducted to evaluate the direct toxicity effect of certain drugs on human renal proximal tubule epithelial cells. Few classes of drugs are known to cause renal failure by preferential accumulation within the proximal tubule cells.  An in vitro study was done to evaluate the toxicity effect of Streptozotocin (a naturally occurring glucosamine-nitrosourea) on human renal proximal tubule epithelial cells from Lonza. The drug showed an upregulation of the activated form of the endoplasmic reticulum stress (ER stress) in the renal epithelial cells.  Elevated ER stress may lead to various kidney maladies.  Chemicals that modulate ER stress are attracting attention due to their potential for clinical application.

Renal models for in vitro toxicity testing

Primary renal epithelial cell cultures have been isolated from human tissue samples. The cells are typically grown under monolayer or 3D conditions in which they form tight junctions and microvilli, express specific cell surface markers and transporters. These renal models from primary cell cultures currently represent the in vitro model closest to the in vivo human environment.  Human primary cells for research applications come from donors whose organs do not meet the transplantation standards. The main advantages with use of these cells include the study of genetic polymorphism influence on drug disposition and action. Such polymorphisms are known to exist for both drug metabolism enzymes such as CYPs and FMOs, and for membrane transporters such as the OATs and P-gp.

Transporter assays using RPTEC cells are usually attempting to test for:

  • Whether drug is a substrate or inhibitor of drug transporter. Interference with transporter function causes adverse effects such as drug accumulation in proximal tubules and adverse drug-drug interactions.
  • What is the appropriate dose and substrate size for optimal renal clearance
  • How drug-drug interactions occur

 
While animal models remain one of the most important tools in preclinical Tox studies, in vitro systems such as culturing primary human cells are becoming increasingly important for decision making in the drug discovery pipeline. Traditionally, immortalized cell lines such as Chinese hamster ovary (CHO) cells, Mardin-Darby canine kidney (MDCK) cells, human embryonic kidney 293 cells (HEK293) and pig kidney epithelial cells (LLC-PK1) have been transfected to over-express a single renal transporter. While these cell lines are easier to grow than primary cells, cell lines have indefinite life span triggering mutations and most of them originate from cancer tissues. Recently, there have also been concerns raised by scientific industry with authentication and identity of these historically utilized cell lines.
 
The use of primary cells can potentially reduce the number of animal studies, their associated costs, alleviate ethical concerns with animal use expressed across many regions of the world.  If targets are screened in a combination of in vivo/in vitro models, the approach also helps realize species-dependent variances seen in cell performance as research shifts between in vivo animal studies and in vitro human models.  For instance, in vitro human-based assays provide closer estimation of clinical outcomes for CYP induction where these enzymes are known to have properties dissimilar between species. 
 
The current trend is to use rats as the first animal species for testing drug exposure because they are inexpensive and require small amount of test compound. Such studies can help identify ADME challenges of a new chemical series, such as whether low absorption or high clearance occurs, leading to undesirable PK. 

Tools for developing your renal models

We offer a variety of primary human renal cell types and REGM™ Renal Epithelial Growth Medium along with protocols and support team to ease your transition into generating biologically relevant in vitro renal models. For diseased cells, detailed donor information can also be requested by contacting our scientific support team. If you have custom requests, please contact our CellBio Services team.

Renal Epithelial Culture

Select references with Lonza's renal cells and media

Renal physiology in ADME-Tox studies:

Intercellular communication is a key process in the development and maintenance of multicellular organisms. Study mentioned here reported extensive spontaneous intercellular exchange of cargo vesicles and organelles between primary human proximal tubular epithelial cells. Sophie Domhan,  Lili Ma, Albert Tai, Zachary Anaya, Afshin Beheshti, Martin Zeier, Lynn Hlatky, Amir Abdollahi. Intercellular Communication by Exchange of Cytoplasmic Material via Tunneling Nano-Tube Like Structures in Primary Human Renal Epithelial Cells. PLoS ONE (2011); 6(6): e21283

Nephrotoxicity studies :

 

Study was done to evaluate the direct toxicity of Streptozotocin on human renal proximal tubule epithelial cells which resulted in upregulation of the activated form of the endoplasmic reticulum stress (ER stress) in the renal epithelial cells. Uetake R, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Iesato Y, Yoshizawa T, Koyama T, Yang L, Toriyama Y, Yamauchi A, Igarashi K, Tanaka M, Kuwabara T, Mori K, Yanagita M, Mukoyama M, Shindo T. Adrenomedullin-RAMP2 system suppresses ER stress-induced tubule cell death and is involved in kidney protection. PLoS ONE (2014); 9(2): e87667

Renal drug transporters ADME-Tox studies :

Study was done using Lonza’s human renal proximal tubule cells (CC-2553), where the effect of Cobicistat (COBI) on the cytotoxicity of  Tenofovir (TFV) in renal cell cultures was examined to elucidate renal drug-drug interaction between these two components. Kirsten M. Stray, Rujuta A. Bam, Gabriel Birkus, Jia Hao, Eve-Irene Lepist, Stephen R. Yant, Adrian S. Ray, Tomas Cihlar.  Evaluation of the effect of cobicistat on the in vitro renal transport and cytotoxicity potential of tenofovir. Antimicrobial Agents and Chemotherapy (2013); 57(10): 4982-4989