Chronic kidney disease project

Fibrosis or accumulation of matrix proteins is a common feature of chronic diseases and aging that accounts for up to 45% of deaths in western countries. From the dawn of biomedical research, reversing organ fibrosis remains the “holy grail” of medicine. Chronic kidney disease (CKD) affects 10% of humans and increases the risk of cardiovascular diseases, and tubulo-interstitial fibrosis (TIF) is the hallmark of CKD that correlates with function loss. Despite considerable progress in understanding the pathophysiology of TIF progression, curative treatment is still out of reach in practice.

The kidney is endowed with an intrinsic regenerative capacity allowing recovery after an acute kidney injury (AKI) and maintenance of life-sustaining renal function in kidney donors and transplant recipients. However, the key molecular contributors and mechanisms in renal post-injury regeneration are still speculative. Our previous studies identified TGF-b/b-catenin as pivotal axis that mediates proximal tubule (PT) adaptive response to chronic injury and mitigates TIF. To uncover the molecular signature of renal regeneration and develop clinically relevant and generalizable strategies to combat TIF, I postulate that renal regenerative program is held by a subset of factors which is required to maintain adaptive responsiveness to injury and self-renewal capacity that I name “parenchymal repair landmarks" (PRLs). Among TGF-b/b-catenin axis targets, N-cadherin acts as potential PT PRL.

Our research focuses on promoting renal parenchyma self-renewal to stop TIF and aims to 1) uncover the cellular and molecular signature of renal regenerative program upon chronic injury and halving renal mass; 2) demonstrate the mechanisms that compromise renal regenerative program in chronic injury; 3) develop therapeutic strategies based on self-renewal capacity of renal parenchyma to mitigate TIF.

We combine novel spatial transcriptomics/biochemistry approaches with acquired knowledge in TGF-b/b-catenin axis and CKD/TIF to uncover PRLs using mouse, axolotl and PT cell models in three specific aims:

Aim 1: Targeting PT PRLs along the TGF-b/b-catenin axis and their therapeutic potential

Aim 2: Determine how N-cadherin affects PT metabolism and response to chronic injury

Aim 3: Investigate the mechanism of renal regeneration in axolotl