Research

Our group has been dealing with animal models of (nephrological) immunological diseases affecting the kidney since 1992. The ultimate common pathway for chronic kidney disease is kidney scarring: to our current knowledge, the progression of renal fibrosis to end-stage renal failure is unstoppable. The only clinically effective treatment is inhibition of the renin-angiotensin system (RAAS). Examining different rat models of renal fibrosis, we found that multi-point inhibition of RAAS or its combination with immunosuppressive agents was more effective in slowing progression than monotherapy.

One common cause of end-stage renal disease and kidney transplantation is an autoimmune disease: kidney disease (lupus nephritis) caused by lupus (SLE). In our mouse model studies, we found that different immunological mechanisms are involved in the organ manifestation of systemic disease, which may justify different treatment of different clinical forms.

Kidney transplantation is the best quality of life treatment for end-stage renal disease. However, the long-term function of transplanted kidneys is limited, the main cause of which is chronic allograft nephropathy. Using experimental treatments in a rat model of kidney transplantation, we found that the process of chronic allograft nephropathy can be divided into two parts: the immune response to the foreign antigen plays an important role in the early stages. One of the main mediators of fibrosis in this stage is transforming growth factor (TGF) beta, which can be effectively influenced by inhibiting inflammatory cell infiltration with immunosuppressive agents, while in the late stage, inflammatory infiltration is replaced by scarring and fibrotic processes. Rather, platelet-derived PDGF and connective tissue growth factor (CTGF) production predominate at this late stage, and inhibition of RAAS is the most effective treatment.

An important factor in the prognosis of kidney transplantation is ischemia-reperfusion injury (IRI) during transplantation. Acute tubular necrosis (ATN), a common cause of IRI, is one of the leading causes of death in the intensive care unit. We observed that in control mice, all fatal renal artery constriction survived in all mice treated with bacterial endotoxin. A significant (80%) improvement in survival was also achieved by inhibiting programmed cell death (apoptosis) during reperfusion. In these experiments, we used the method of gene silencing for the first time in the world to treat a kidney in a live animal.

Gene silencing, a new form of gene therapy, is currently in the focus of scientific interest. The advantage is that the production of a given protein can be inhibited very efficiently, in a targeted and permanent manner without altering the genetic code. At the same time, the delivery of the short nucleic acid (RNA) molecules used to cells is hampered. More recently, it has been recognized that cells regulate their own protein production by a similar mechanism using microRNAs (miRNAs). We are currently investigating altered miRNA production during renal ischemia-reperfusion injury and its possible diagnostic and therapeutic implications.

Breast cancer is one of the most frequent cancer types among women worldwide. Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer type with very poor survival due to the lack of targeted therapy. The most commonly used mouse TNBC models utilize cell lines derived from mouse mammary carcinoma cell line 410.4 isolated from a single spontaneous tumor in Balb/c mice. Cell lines 4T1 and 4T07 are the most aggressive and invasive sub-clones derived from the 410.4 cell line. Implantation of these cell lines creates isografts in Balb/c mice. Thus, after the inoculation of syngeneic cells, immune mechanisms can be investigated under conditions very similar to those of human TNBC.

Modulated electro-hyperthermia (mEHT) is a newly emerging adjuvant cancer treatment used in human oncology, with strong cancer inhibitory effect in monotherapy in our mouse model. During mEHT, a focused electromagnetic field (EMF) is generated within the tumor, by applying capacitive radiofrequency. Selective energy absorption by the tumor is the consequence of its elevated oxidative glycolysis (Warburg effect) and conductivity. The EMF induces cell death by thermal and non-thermal effects. Capacitive energy delivery and frequency modulation enable the application of non-thermal effects. Within the framework of NVKP_16-1-2016-0042 grant we have developed the rodent mEHT device to enable accurate, reproducible, standard and effective treatment of TNBC in the inguinal region of mice. Selective energy absorption enabled +2.5 °C heating of the tumor a great advantage over former hyperthermia methods, where the temperature difference between tumor and surrounding tissues was only +1°C. Thus, the thermal and non-thermal effects amplify each other leading to effective tumor cell killing. The device is also useful to deliver therapeutic agents locally by using thermo-sensitive liposomes (TSL). Lea Danics received “the most innovative PhD thesis” price for the development and first utilization of the rodent-specific mEHT device.