The Era of MicroRNAs

Khella et al AJKD

Fig 3 from Khella et al.

Research related to microRNAs (miRNAs) is a new and rapidly expanding area. The application of miRNA measurement and their role in physiology and pathophysiology in kidney diseases is the topic of a recent review published in the American Journal of Kidney Diseases. Co-author Dr. George Yousef (GY), from the Department of Laboratory Medicine and Pathobiology, St. Michael’s Hospital and the University of Toronto, discusses this review with Dr. Matthew Sparks (eAJKD), eAJKD Advisory Board member.

eAJKD: Can you briefly describe what miRNAs are?

GY: miRNAs are small fragments of single-stranded RNA fragments of about 20 to 25 nucleotides in length that are synthesized in the nucleus and then transported into the cytoplasm. They are not good for encoding proteins, but rather function by targeting other genes. Recent evidence has shown that miRNAs may have a major role in vital cellular processes, including cell maturation, differentiation, and apoptosis.

eAJKD: Where is the field of nephrology with research into miRNAs?

GY: There is a growing body of literature with regard to miRNAs in diabetic kidney disease and hypertension. Progress in this area is slow, likely due to the difficulty in obtaining enough biopsy specimens, and the complexity and chronicity of the pathogenesis. Furthermore, many kidney diseases have complex etiologies with a low prevalence so that it is difficult to identify an adequate number of patients to study.

eAJKD: You describe in your paper how miRNAs can be used as a prognostic marker for renal cell carcinoma. Can you briefly discuss this?

GY: Renal cell carcinoma (RCC) is an aggressive disease with a 65% five-year survival rate. Predicting how aggressive a patient’s malignancy is becomes a key factor toward individualizing their treatment plan. Data from our lab and from other labs has shown the promise of a few miRNAs like miR-21, miR-215, and others as prognostic markers for RCC. This is supported by experimental evidence that links these miRNAs to the aggressiveness of the disease through stem cell or tumor enhancing characteristics. In the future, these miRNAs could be used either alone or in combination with other histopathologic parameters to accurately plot the prognosis of the disease. For now, we can measure them in tissues, but the hope is that in the near future a blood or urine test will be developed.

eAJKD: Are there any data looking at targeting “pathologic miRNAs” in kidney disease or RCC?

GY: There is preliminary data that shows altering expression levels of certain miRNAs might have a therapeutic impact. For example, suppressing miR-21 can significantly affect the rate of fibrosis, which is a common problem in many of the kidney diseases. Another miRNA, miR-155, has been shown to have an effect on controlling blood pressure. In kidney cancer, certain miRNAs (termed oncogenic miRNAs) have the ability to give the tumor stem cell-like characteristics that enhance migration. Most of this data is derived from cell lines, but it is encouraging that targeting these miRNAs in vitro significantly reduces the rate of tumor growth and proliferation. Our hopes are that this will soon be translated to whole animal models and eventually humans.

eAJKD:What are some of the challenges to miRNA research, and potential use in humans?

GY: Understanding the physiologic role of miRNAs is a key issue in the future of miRNA research. This includes the identification and experimental validation of miRNA target genes. We also need to move forward and perform in vivo validation studies of the in vitro cell line models. Technical issues have to be considered, and these include standardizing miRNA testing in tissues or other body fluids and understanding how relative differences in expression relate to function. These are challenging issues because of the extremely small size of miRNAs and the high degree of homology between different miRNAs.

eAJKD: Do you see miRNAs being used in clinical medicine, either as a prognostic tool or as a therapeutic tool, in the next several years?

GY: Our group is a strong believer that very soon miRNAs will have a strong impact on patient management. We can foresee the use of specific miRNAs as tumor markers, either as a diagnostic or prognostic tool. Interestingly, you can insolate miRNAs from paraffin-embedded tissues or from serum, urine, and other body fluids. In addition to this, there is ongoing research using miRNA in therapy. miRNAs have a number of advantages for treatment. For example, they are small molecules that simultaneously target multiple genes. They are less toxic and can penetrate a variety of tissues and body organs. We believe that miRNAs hold a lot of promise to treat a variety of diseases.

eAJKD: Do you have any final comments about miRNAs?

GY: As the title of our manuscript implies, we are just scratching the surface of our understanding of miRNA research. We, as a research community, are still collecting all the pieces of the puzzle. We are hopeful that in the near future we will generate meaningful uses of miRNAs in disease processes, and understand in more depth how these molecules interact and with other types of molecules to produce a disease phenotype.

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