Mechanisms of polycystic kidney diseases
(Group leader: Rudolf Wüthrich)
Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary cause of end-stage renal disease. Mutations in the genes encoding for polycystin-1 (PKD1) or polycystin-2 (PKD2) lead to alterations of various signalling cascades in tubular epithelial cells and cause the cystic disease. Despite decades of intense research no effective treatment exists which retards or reverses cyst growth in patients affected by ADPKD.
Inhibition of the renal sodium-glucose cotransporter SGLT2 in renal proximal tubules with derivatives of phlorizin such as dapagloflozin results in marked glycosuria. The purpose of our current research is to test whether inhibition of SGLT2 has a beneficial effect on disease progression in animal models of polycystic kidney disease and in patients with ADPKD.
Role of non-coding RNAs in kidney injury
(Group Leader: Johan Lorenzen)
Our group is interested in the mechanisms of kidney injury mediated by non-coding RNAs. Merely 1 - 2% of the human genome is transcribed into RNA transcripts, which are subsequently translated into protein. The remainder (>98%) are so called non-coding RNAs (ncRNAs), which are arbitrarily separated into long ncRNAs (lncRNAs, ≥ 200 nucleotides) and small ncRNAs (≤200 nucleotides).
Small RNAs including microRNAs, which lead to the repression of gene/protein expression and/or translational inhibition of protein synthesis by post-transcriptional binding of the 3’-untranslated region (UTR) of mRNA targets, have been extensively studied over the past several years. MicroRNAs are important mediators of tissue homeostasis under various pathological conditions and are of potential therapeutic relevance.
These short, non-coding nucleotides have a length of ~22 nucleotides. More than 1000 miRNAs regulate a considerable amount of the human genome and are involved in virtually all biological processes, including cellular proliferation, apoptosis and differentiation. Thus, miRNA deregulation often results in impaired cellular function and development of disease. In contrast to microRNAs, little is known about the functional role of lncRNAs.
However, studies over the past 5 years have shown that lncRNAs interfere with various physiological and pathological processes. Putative roles for lncRNAs have been identified in conditions such as heart failure, cardiac autophagy, hypertension, acute kidney injury, glomerular diseases, acute allograft rejection and renal cell carcinoma. We aim to identify novel non-coding RNAs in different mouse models of kidney injury and elucidate involved signaling pathways in vivo and in vitro.
We are interested in modulating pathological non-coding RNA expression by RNA therapeutics, which enable specific targeting and cleavage of non-coding RNAs and thus modulation of pathological signaling pathways in vivo. In addition, non-coding RNAs are released into the extracellular compartment (blood and urine) in patients. Thus, circulating non-coding RNAs may serve as a non-invasive tool to detect and monitor disease activity. In several clinical projects we aim to investigate the release pattern of circulating non-coding RNAs.
Mechanisms of proteinuria and glomerular injury
(Group leader: Andreas Kistler)
Andreas Kistler is a senior nephrologist with a clinical focus on glomerular diseases and renal manifestations of vasculitides. The laboratory focusses on the pathogenesis of proteinuria with a main focus on immune-mediated mechanisms of podocyte injury.
Current project: in vivo and in vitro models of membranous nephropathy Idiopathic membranous nephropathy (iMN) is an antibody mediated autoimmune kidney disease caused by autoantibodies against PLA2R or other autoantigens on podocytes, a cell type that is central to maintaining the kidney filter barrier. We aim to establish in vivo and in vitro models for this disease using assays based on (a) cultured podocytes, (b) in vivo expression of the target antigens in rodents and (c) transplantation of human glomeruli into mice (in collaboration with University of Miami).