Highlighting RNA-binding proteins and their role in kidney disease as potential therapeutic targets

Many RNA-binding proteins (RBPs) are dysregulated in kidney diseases, involved in disease pathogenesis and/or associated with disease severity. Two examples: a) Acute kidney injury (AKI). b) Polycystic kidney disease (PKD). doi: https://doi.org/10.1038/s41581-021-00497-1

Research on the interaction between proteins has been a focus of many groups both in basic and medical science in the past. Much less is known about the contribution of RNA-protein interactions to human disease.

The human genome contains more than 1,000 RNA-binding proteins (RBPs), which are involved in every step of the RNA life cycle and have a major impact on cellular biology. Given the central role of RBPs in RNA metabolism and cellular biology, the fact that various RBPs are involved in glomerular and tubular kidney pathologies is unsurprising. Indeed, it seems likely that RBPs have roles in all kidney diseases.

• RBPs have been shown to have roles in tubular and glomerular kidney diseases, including acute kidney injury (AKI), chronic kidney disease, kidney fibrosis, polycystic kidney disease (PKD), diabetic kidney disease and glomerulonephritis.
• RBPs can have both protective and pathogenic roles in kidney diseases; for example, two of the best studied RBPs — HuR and YBX1 — ameliorate damage in AKI but promote kidney fibrosis.
• The role of RBPs in kidney disorders is conserved throughout evolution; for example, mutations in BICC1 lead to a cystic phenotype of the Malpigian tubules in Drosophila melanogaster and are associated with PKD in vertebrates.
• Environmental changes that are associated with renal pathophysiology, such as hypo-osmolality or hypoxia, can modulate RNA–protein interactions.
• RNA–protein interactions can be inhibited and are potential therapeutic targets for various kidney diseases.

Cologne researchers from the Department of Internal Medicine at the Faculty of Medicine, University of Cologne and the University Hospital and affiliated with the Center for Molecular Medicine Cologne as well as CECAD Cologne provide a concise overview of the current knowledge of RBPs and their interactions with mRNA, non-coding RNA (ncRNA) and proteins, as well as their specific roles in kidney diseases and their potential as novel therapeutic targets. The work was published in Nature Reviews of Nephrology (Nov. 03, 2021) - DOI https://doi.org/10.1038/s41581-021-00497-1  or  https://rdcu.be/cBaSp  This link will allow readers who do not have a subscription to the journal to freely access the full text of the review.

"RNA-binding proteins (RBPs) are of fundamental importance for post-transcriptional gene regulation and protein synthesis. They are required for pre-mRNA processing and for RNA transport, degradation and translation into protein, and can regulate every step in the life cycle of their RNA targets. In addition, RBP function can be modulated by RNA binding. RBPs also participate in the formation of ribonucleoprotein complexes that build up macromolecular machineries such as the ribosome and spliceosome", Michael Ignarski says.

"Although most research has focused on mRNA-binding proteins, non-coding RNAs are also regulated and sequestered by RBPs. Functional defects and changes in the expression levels of RBPs have been implicated in numerous diseases, including neurological disorders, muscular atrophy and cancers", Roman-Ulrich Müller comments.

"RBPs also contribute to a wide spectrum of kidney disorders. For example, human antigen R has been reported to have a renoprotective function in acute kidney injury (AKI) but might also contribute to the development of glomerulosclerosis, tubulointerstitial fibrosis and diabetic kidney disease (DKD), loss of bicaudal C is associated with cystic kidney diseases and Y-box binding protein 1 has been implicated in the pathogenesis of AKI, DKD and glomerular disorders", Ignarski explains.

"Taking into account the exponential increase in knowledge on RBPs in the kidney that is facilitated by the use of novel technologies to capture RPBs together with their target RNAs, we are excited to highlight the remarkable opportunity for kidney research", Müller says.
Characterizing RNA–protein interactions is not only important to improving understanding of renal pathophysiology, but also to potentially providing entirely new therapeutic opportunities.

Original Publication:
RNA- binding proteins and their role in kidney disease - Nat Rev Nephrol. 2021 Nov 3. doi: https://doi.org/10.1038/s41581-021-00497-1
Lisa Seufert^1,2, Thomas Benzing^1,2, Michael Ignarski^1,2,3, and Roman-Ulrich Müller^1,2,3
1Dept. II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, DE
²CECAD, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, DE
³These authors contributed equally

Scientific Contact:
Dr. med. Roman-Ulrich Müller (roman-ulrich.mueller[at]uk-koeln.de)
Dr. med. Michael Ignarski (michael.ignarski[at]uk-koeln.de)
nephrolab Cologne
Klinik II für Innere Medizin