Scientists at Nanyang Technological University, Singapore (NTU Singapore) have successfully grown “mini-kidneys” in the laboratory and grafted them into live mice, revealing new insights into metabolic defects and a potential therapy for polycystic kidney disease.
‘Mini kidneys’ or renal organoids are kidney-like structures grown in the laboratory using stem cells. In the study led by NTU’s Lee Kong Chian College of Medicine (LKCMedicine), researchers grew the organoids using skin cells derived from patients with polycystic kidney disease (PKD), a prevalent form of the genetic condition that affects 1 of every 1,000 people of all ethnicities. *
People with PKD often progress to end-stage kidney disease between the ages of 50 and 60, and the standard treatment options available are dialysis or a kidney transplant. However, dialysis significantly compromises the patient’s quality of life, while acquiring a transplanted kidney can be difficult. Another option is the Food and Drug Administration (FDA)-approved drug Tolvaptan, which is very expensive and has serious side effects on the liver.
To address the need for a more effective treatment for PKD patients, the NTU research team sought to better understand the disease by grafting their newly developed mini-kidneys into mice.
Previous studies were conducted with mini-kidneys grown in a dish, which could only partially mimic the structure and function of the kidney. NTU scientists grafted mini-kidneys into live mice to comprehensively replicate the pathological features of kidney disease, including blood flow, fluid movement (tubular fluid), and cellular communication with other organs.
Lead researcher, Assistant Professor Xia Yun from LKCMedicine, said: “Grafting the kidney organoid in mice provided us with a physiologically sophisticated approach to studying PKD, as we were able to successfully emulate critical features of the disease similar to those seen in human kidney patients”.
Critical features of the disease included abnormalities such as the spontaneous formation of cysts in the kidneys and subsequent damage to their tiny tubes.
In his study, published in the scientific journal cell stem cell, the NTU research team said they believed their grafted mini-kidneys were of high quality because the cysts were maintained without additional stress stimulation or chemicals, even after they were removed from the live mice for further research in a dish. In contrast, previous renal organoids cultured in a dish cannot form cysts without stress stimulation.
Co-investigator Assistant Professor Foo Jia Nee from LKCMedicine said: “The similarity between the disease manifestation observed in our grafted mini-kidney model and the real-life experiences of patients with polycystic kidney disease suggests that culturing kidney organoids and grafting them into live mice “could be beneficial for studying the disease and a useful tool for testing new treatments.”
Metabolic defects in polycystic kidney disease
Scientists have long known that abnormalities in a kidney cell structure, or the primary cilium, cause cysts to form in the kidneys. However, so far no evidence has been possible to understand the regulatory mechanism and relationship between primary cilium and cellular metabolism (autophagy) in living PKD mice.
By studying the development of PKD in live mice and testing cellular pathways, the researchers found evidence that boosting autophagy could reduce the severity of mini-kidney cysts.
After establishing that boosting autophagy could reduce cysts, NTU scientists shortlisted 22 drugs known for their effects on cellular metabolism and tested them in the laboratory. The results showed that minoxidil, a clinical drug widely used to cure hypertension and hair loss, effectively reduced cyst formation in the new mouse model.
Associate Professor Xia Yun said: “Our study has shown how cysts in kidneys with polycystic diseases can be reduced by increasing autophagy, suggesting that this could be a promising treatment for PKD. Furthermore, clinical safety proven benefit of minoxidil can allow you to recover quickly. “It is intended to treat patients with PKD in the clinic. However, more research will be needed to establish this potential.”
As an independent expert, Associate Professor Ng Kar Hui, Senior Consultant, Division of Pediatric Nephrology, Dialysis and Renal Transplantation, Department of Pediatrics, Khoo Teck Puat – National University Children’s Medical Institute, National University Hospital, said: “Kidney disease polycystic disease “It is one of the main causes of chronic kidney disease among adults. Effective treatment could improve the growing number of people with kidney failure in Singapore. “Establishing such models in living organisms brings us one step closer to finding more treatment options.”
In future studies, the NTU team will test the efficacy of minoxidil and adapt mini-kidney models to investigate other burgeoning kidney diseases without a strong genetic basis, such as diabetic kidney disease.
* Harris, PC and Torres, VE (2009). Polycystic kidney disease. Annual Journal of Medicine. Volume 60, 321-337.