The kidney and urinary systems play an essential role in maintaining the homeostasis of the body’s internal environment by filtering the blood to remove nitrogen wastes (as urine collected in the bladder), regulating fluid and electrolyte levels, as well as participating in drug transport/metabolism and secreting critical endocrine factors. The nephrons are the primary filtration unit of the kidneys and it is the epithelial cells located within these structures that exert the kidney’s functional effects on the body’s physiological processes. In vitro urinary excretory cell culture systems are, therefore, valuable research tools for investigating a multitude of research applications such as studying in vivo physiology, kidney and bladder cancer modeling, drug ADME (absorption, distribution, metabolism, and excretion) studies, and more.

Drug Cytotoxicity Testing

We kicked off 2021 with a blog discussing the usage of Lifeline’s Normal Human Renal Epithelial Cells for drug cytotoxicity studies of a recently approved antiviral therapeutic for COVID-19 (click here for more details). The authors utilized Normal Human Renal Proximal Tubule Cells (RPTEC’s) along with other relevant human primary cells and cell lines to establish the in vitro drug safety profile of remdesivir (RDV) and its metabolites and identify any off-target toxicities using a series of cellular and biochemical assays. The high selective index (CC50 values ranged from 1.7 to > 20 μM) of RDV combined with its low IC50 of 9.9 nM (concentration needed to inhibit the 50% of the virus) of RDV with respect to its anti-SARS-CoV-2 activity led the authors to conclude that RDV’s beneficial clinical effect in treating COVID-19 far outweighed the low potential for off-target toxicities.

Discovery of a Uremic Toxin Involved in the Development of Chronic Kidney Disease

The CDC estimated that 37 million individuals in the US are affected by chronic kidney disease. This develops when the kidneys become damaged and are unable to function properly, resulting in a buildup of waste products like uremic toxins in the body, which can lead to a host of other health issues. In a publication by Okada and colleagues reviewed in a 2020 Lifeline blog, the role of plasma D-serine (an amino acid-derived waste product) as a novel uremic toxin in the progression of chronic kidney disease was investigated using both HK-2 cells (an immortalized human proximal tubular cell line) and Lifeline normal human renal epithelial cells (RPTEC’s). The authors determined that D-serine decreased cell proliferation and increase apoptosis of RPTEC’s through activation of integrated stress response (ISR) pathways. The resulting renal tubular cell senescence is a major contributor to the kidney damage observed in the development of chronic kidney disease.

Discovery of New Chemotherapeutic with Selective Toxicity for Renal Cancer Cells

The ability to target and kill cancer cells without damaging the surrounding healthy cells is a major challenge when developing chemotherapeutic drugs. To test the efficacy of a new chemotherapeutic, it is important to have normal, healthy cells as controls to elucidate any off-target toxicities. In a publication by Fernández-Gallardo and colleagues, reviewed in the blog linked here, Lifeline’s normal human renal proximal tubular cells were used as control cells to examine the efficacy and target cell specificity of heterometallic titanium-gold complexes as a chemotherapeutic for renal cell carcinoma. The researchers discovered that the heterometallic compounds, in particular compound 5, exhibited toxicity to renal carcinoma cell lines, while exerting minimal toxicity on normal renal proximal tubular cells. Compound 5 was found to block renal cancer growth by inhibiting thioredoxin reductase, an enzyme integral to cell growth and survival, and proteins kinases involved in cell migration. Combined, the potent anti-tumor activity and selective toxicity towards renal cancer cells meets the researcher’s goal of developing chemotherapeutic drugs that are effective with minimal side effects on normal cells in contrast to current clinical compounds for renal carcinoma like cisplatin, which show a high toxicity for normal and cancerous renal cells.

Elucidating the Method of Action for a Bladder Cancer Therapeutic Candidate

Research by Knowles and colleagues, reviewed in a Lifeline blog linked here, summarize the potential use of the anti-angiogenic peptide CLT1 as a promising treatment for bladder and other cancers. To understand the mechanism by which CLT1’s exerts its anti-angiogenic activity, a variety of immunological and biological assays were performed on a panel of bladder tumor cell lines (and normal bladder control cells) as well as a variety of cell lines derived from kidney, lung, breast and prostate cancer. The researchers found that CLT1 induces tumor cell death in a cooperative manner with fibronectin, which complexes with CLT1 to promote CLT1 uptake into endothelial cells of angiogenic blood vessels to induce autophagic cell death. A mechanistic link between CLT1/fibronectin and tumor cell integrin α5β1 and chloride intracellular channel 3 (CLIC3) was confirmed by the upregulation of α5β1 and CLIC3 genes in CLT1-responsive tumor cell lines as well as the in vivo co-localization of these molecules with CLT1 in tumor tissues. Additionally, while CLT1 treatment inhibited angiogenesis and bladder tumor growth in tumor cell lines, it did not induce toxicity in normal, healthy bladder epithelial cells indicating that CLT1 could be a potent therapeutic for targeting bladder cancer.

If you are interested in renal or bladder cells for your own research, please see the Lifeline catalog for more information:

• Human Renal Medullary Epithelial Cells
• Human Renal Proximal Tubule Epithelial Cells
• Human Renal Cortical Epithelial Cells
• Human Renal Mixed Epithelial Cells
• Human Bladder Apex Epithelial Cells
• Human Bladder Dome Epithelial Cells
• Human Bladder Smooth Muscle Cells
• Human Bladder Fibroblasts

Visit us here at our blog every other week to learn more about our portfolio of human cells and culture media, which are helping researchers around the world answer their scientific questions. Have you used our cells? Let us know and your study could be featured here on the blog!