Research Award Recipients
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Paul Isenring | Laval University

Type of Funding Awarded: Kidney Health Research Grants

Molecular mechanisms and therapeutic strategies in ADTKD-REN(L16del)

Lay Abstract

Background: This proposal is concerned with a kidney disease that runs in a large family. The genetic defect at cause appears to consist of a missing amino acid in a protein called renin. It will be called the LEU16DEL/REN mutation from now on. However, it is believed to be quite uncommon in the population, and its impact on the protein has not been studied carefully. All individuals who have a disease-causing mutation in the renin gene appear to develop some form of chronic kidney disease (CKD). Standard of care for this condition is still limited to supportive measures. We have recently identified a large cohort of individuals who are affected by the LEU16DEL/REN mutation. This cohort comes from a single pedigree of over 2000 members across 6 generations. Among 117 individuals (from 3 lineages out of 12) who were investigated in the pedigree uncovered, 66 were found to have the mutation along with CKD and 51 to be affected by neither the mutation nor CKD. Based on these numbers, CKD arising from the LEU16DEL/REN mutation could thus be much more common than foreseen in our Province. In the last several months, we have also identified some clues as to how the LEU16DEL/REN mutation causes CKD and how its repercussions could be cured through the use of drugs.

Purpose: In the light of these premises, we wish to establish formal linkage between the LEU16DEL/REN mutation and CKD in the pedigree and to confirm our initial findings in regard to the mechanisms of disease development and potential therapeutic avenues.

Method: We plan to tackle the objectives pursued through the use of cell lines derived from the kidney. These cell lines will be made to express the LEU16DEL renin mutant to determine how and why they are affected by it. They will also be treated with the drugs identified to determine whether they can be kept healthy in spite of the LEU16DEL/REN mutation. In future grant terms, the gene defect will be introduced in a mouse model to study its effects in vivo and to determine whether the same drugs can be useful in halting the progression of CKD or preventing this complication from occurring. Anticipated outcome. We expect the identified mutation to be entirely responsible for the disease and to exert its effects by damaging certain types of kidney cells. We also anticipate that the adverse consequences of the mutation could be counteracted by therapies aimed at restoring the mutant to a healthier state or preventing it from recruiting destructive intermediates.

Relevance to patients/community: The studies proposed could be of tremendous benefit to the CKD population of Canada. In particular, they could lead the way to the development of drugs that would decrease the progression of CKD and the need for dialysis in patients carrying the LEU16DEL/REN mutation. Since this mutation is highly prevalent in Quebec, and chronic kidney failure makes individuals very ill or can be fatal, the quality of life and survival of thousands of Quebecers and Canadians could be greatly improved through medications that are active in preventing the deleterious effects of the LEU16DEL/REN mutation. Conclusion. Our studies are essential to understand the reasons why the LEU16DEL/REN mutation leads to renal failure and how its deleterious effects can be counteracted. Efforts aimed at furthering our knowledge in these regards hold the promise of decreasing the burden of renal failure in our Province of Québec and in Canada as well.