The impact of miR-193a on the pathogenesis of FSGS

Focal segmental glomerulosclerosis (FSGS) is one of the most frequent glomerular diseases in adults. It is characterised by focal and segmental sclerosis of the kidney glomeruli and profuse podocyte (visceral epithelial cells) foot process effacement. The resulting kidney damage is progressive and irresponsive to treatment and leads to the nephrotic syndrome with proteinuria, hypoalbuminaemia and oedema, followed by kidney failure. While for a limited number of cases genetic mutations in podocyte-specific genes, drugs, viruses or a circulating factor are responsible, for the majority of cases the cause is not understood in detail. Recently, we have identified miR-193a as a main candidate for podocyte damage in human FSGS patients. miR-193a suppressed its target Wilms Tumor 1 (WT1), a master regulator of kidney development and podocyte homeostasis. This led to loss of the podocyte proteins Podocalyxin and Nephrin and induced FSGS. These findings represent a big step towards the elucidation of so far idiopathic FSGS cases and the first efficient and specific therapy and require a more thorough analysis of the miR-193a pathway in podocytes. The main goal of this project is the identification and characterisation of upstream events that increase the expression of miR-193a in FSGS patients. Downstream of miR-193a, we want to elucidate if targets other than WT1 also have a significant contribution to FSGS in vivo with a special focus on ATOH8. Based on these insights, we want to optimise our therapeutic approach with tiny LNAs inhibiting miR-193a in vivo, if available also in models other than our own miR-193a over-expressing transgenic mice.

Focal Segmental Glomerulosclerosis (FSGS) is a severe kidney disease that can be caused by many different etiologies. Patients suffer from strong loss of protein in urine and progressively lose kidney function. For a high number of patients therapy is still lacking and dialysis or kidney transplantation remain as the last ressorts. Therefore, it is of utmost importance to understand the molecular causes of the disease better and develop novel therapies. With our research we could describe changes in mRNA expression in podocytes and in protein composition of the extra-cellular matrix. Supported by a computer-algorithm we were able to predict and test a novek FSGS therapy. Podocytes are highly differentiated cells and central for the filtration of blood. Pathological changes in podocytes are central for FSGS. By using the so-called miR-193 mouse model, we could define specific changes in signal pathways in podocytes (Wnt, ECM, circadian genes). Interestingly, podocyte-specific genes were not changed. This was a surprising finding and could change our view on FSGS and suggest additional therapeutic options. In another project using the same mouse model we analysed the sclerotic process, which is the ultimate reason for kidney failure in FSGS. We found that in the ECM a very strong increase in fibrinogen and complement components. That knowledge can be used to develop novel therapeutic approaches. In a further project we tested if a modulator of the immune system (Anakinra) could ameliorate FSGS as Anakinra influences pathways also relevant for FSGS. After testing it in a mouse model, we would not recommend its use for human therapy. In another unpublished project we could show that oveerexpression of a gene, that is also increased in FSGS patients, can cause FSGS. This represents the establishment of a new FSGS model as well as the possibility to develop novel therapeutic approaches. In conclusion, in different projects we extended the knowledge of FSGS and options for new therapies.