Research

The role of DNA damage response signaling in chronic kidney disease

Prinicipal Investigator

Dr. Markus Schüler

Scientific interest within the context of the graduate college:

Our research group studies the underlying mechanisms of chronic kidney disease (CKD). Acute and chronic kidney injury has been increasingly recognized as a global public health concern, associated with high morbidity, and mortality. Acute kidney injury is frequent, occurring in 21% of hospital admissions and leads to CKD regardless of the cause. CKD encompasses a group of heterogeneous disorders affecting renal structure and function with a prevalence of 10-15% worldwide1. During the past decades, research into kidney disease has largely focused on identifying causative insults and disease modifiers of renal injury. However, sufficient clarification about the underlying pathophysiological mechanism has not provided yet.

We hypothesize that the ability of the kidney to respond to different stress conditions contributes significantly to the maintenance of normal renal function and structure, whereas an impaired cellular stress responses promotes renal damage. Here, we focus on the so-called “DNA Damage Response” (DDR)2, which relevance for kidney diseases has been demonstrated in individuals with interstitial nephritis caused by monogenic mutations in genes encoding proteins of the DDR complex3. Interestingly, transgenic mice models with a defective DDR response show an increased susceptibility to environmental nephrotoxins, which leads to renal failure and typical histological features of CKD4. Moreover, recently published data argues that DDR functions are critical in disease progression of rare, inherited juvenile nephropathies as evidenced by accumulated DNA damage, that yields to increase apoptosis coupled with profibrotic responses5,6. This projects aims to investigate if an impaired DNA damage response contributes to the renal pathomechanisms of AKI and CKD.

Project description:

In CKD, regardless of its cause, renal fibrosis is the primary determinant of end-stage kidney disease, with no effective therapy available today. Within in scope of this project it is planned to study the response of kidney tubular cells to DNA damage, which may play a role in the pathophysiology of CKD. Therefore, we employed a human in-vitro model using patient derived renal tubular cells from urine samples, which allows investigating the biological impact of DNA damage response signaling. In a comparative approach, cultured renal tubular cells from individuals with CKD and healthy controls will be used to study the cellular response by applying different molecular techniques. In detail, it is planned to evaluate the activity of the DDR pathway targeting e.g. the accumulation of DNA damage, the cell cycle progression, the rate of apoptosis and profibrotic gene expression profiles. This project provides a new cellular model to study disease mechanisms of acute and chronic kidney injury and may offer new understandings about the pathogenesis of CKD.

Application details

References

  1. Eckardt KU, Coresh J, Devuyst O, […], Köttgen A, Levey AS, Levin A. Evolving importance of kidney disease: from subspecialty to global health burden. Lancet. 2013; 382:158-169. doi:10.1016/S0140-6736(13)60439-0.
  2. Ciccia A, Elledge SJ. The DNA damage response: making it safe to play with knives. Mol Cell. 2010; 40:179-204. doi:10.1016/j.molcel.2010.09.019.
  3. Zhou W, Otto EA, Cluckey A, […], Levy S, Smorgorzewska A, Hildebrandt F. FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair. Nat Genet. 2012; 44:910-915. doi:10.1038/ng.2347.
  4. Airik R, Schueler M, Airik M, […], Mukherjee E, Sims-Lucas S, Hildebrandt F. A FANCD2/FANCI-Associated Nuclease 1-Knockout Model Develops Karyomegalic Interstitial Nephritis. J Am Soc Nephrol. 2016; 27:3552-3559. doi:10.1681/ASN.2015101108.
  5. Chaki M, Airik R, Ghosh AK, […], Smogorzewska A, Otto EA, Hildebrand F. Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling. Cell. 2012; 150:533-548. doi:10.1016/j.cell.2012.06.028.
  6. Slaats GG, Giles RH. Are renal ciliopathies (replication) stressed out? Trends Cell Biol. 2015; 25:317-319. doi:10.1016/j.tcb.2015.03.005.