Quantifying microvascular damage in proteinuric kidney disease

Synopsis:

With this application for joint seed funding, we seek to combine the expertise of Prof. de Seigneux’s group (UNIGE) in chronic kidney disease (CKD) with the know-how of Prof. Kurtcuoglu’s group (UZH) on renal imaging and computational modeling to lay the basis for long-term collaboration. The short-term outcome will be an application for funding to the Swiss National Science Foundation.

Project plan:

Klotho is a protein produced in kidney tubular cells. It plays an important role in balancing phosphate, acting as antioxidant and in cardiovascular health. Loss of klotho is a crucial factor involved in both progression of chronic kidney disease (CKD) and associated cardiovascular complications. ATF3 and ATF4 are gene transcription factors involved in cell survival. They play a protective role in acute kidney injury, are markers of tubular injury, and act as regulators of endothelial cell to fibroblast differentiation during fibrosis.

In a recent study, the de Seigneux group demonstrated that in acute and chronic proteinuria (excess loss of protein through urine), ATF3 and ATF4 production is increased while klotho production is decreased. They further identified the binding site of ATF3 to the klotho promoter and confirmed that ATF3 and ATF4 binding decreases klotho transcription.

In our collaboration, we plan to use ATF3 and ATF4 knock-out mice to study the impact of deficiency of these transcription factors on the development of renal fibrosis, klotho expression and damage of the microvasculature in the context of proteinuric kidney disease. To this end, the de Seigneux group will carry out the animal experiments, while the Kurtcuoglu group will assess changes in the mouse kidneys by imaging and computational analysis. We will apply to the SNSF for funding to carry out this work (PI: de Seigneux).

In preparation of that application, we will perform a pilot study for which we are herewith applying for joint seed funding. This pilot will provide high-resolution structural information on proteinuric kidneys, which will serve as the basis to calculate the number of animals needed in the full study, and will further serve to demonstrate our state of the art. The specific planned activities are

  1. Scan the vascular structure of mouse kidneys with proteinuria using contrast-enhanced X-ray microcomputed tomography (microCT)
  2. Quantify vascular damage by computational image analysis
  3. Identify potential organizational or scientific risks to include in the study plan of the full proposal
  4. Write the sections of the proposal pertinent to the envisioned collaboration

Participants:

Prof. Vartan Kurtcuoglu, University of Zurich
Prof. Sophie De Seigneux, University of Geneva