Podocyte lncRNAs – a novel player in focal-segmental glomerulosclerosis

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Non-coding RNAs play an important role both in cellular biology and physiology of numerous tissues and have been linked to several renal pathologies. Large-scale datasets generated by novel sequencing technologies have shown that the majority of transcripts does indeed not possess any coding potential. Among these non-coding transcripts, long non-coding RNAs (lncRNAs) have gained increasing attention due to numerous studies underlining their importance in organ development and disease. However, a large gap has remained between the growing knowledge on lncRNA expression and the question how these transcripts impact on organ function and disease and how they act on the molecular level. It is in fact this knowledge which would be crucial for a better understanding of their contribution to human disease as well as their exploitation as potential therapeutic targets. As to the role of lncRNAs in kidney disease in general only very little is known; regarding podocyte cell biology and associated diseases such as FSGS we lack virtually any insight at all. As a consequence, the emerging field of lncRNAs bears a great potential for identifying novel diagnostic and therapeutic targets by unraveling associated regulatory processes and their impact on renal pathologies. To reach this goal, we have established a bioinformatic pipeline (CALINCA) which allows for the automated identification of lncRNAs that are podocyte-specific, conserved in evolution and dysregulated in FSGS models. Based on these analyses, we have selected several lncRNAs as promising candidates in the pathogenesis of FSGS and have both created novel knockout mouse lines as well as identified optimal cell culture models for these genes. Here, we propose to unravel the role of these lncRNAs in the pathophysiology of FSGS by (1) examining their molecular function in cell culture and murine kidney tissue, (2) characterizing their impact on the pathogenesis and severity of FSGS in mouse models, and (3) evaluating lncRNA expression patterns and localization as a diagnostic marker in patient samples.