Podocyte Regeneration Driven by Renal Progenitors Determines Glomerular Disease Remission and Can Be Pharmacologically Enhanced

Laura Lasagni,Maria Lucia Angelotti,Elisa Ronconi,Duccio Lombardi,Sara Nardi,Anna Peired,Francesca Becherucci,Benedetta Mazzinghi,Alessandro Sisti,Simone Romoli,Alexa Burger,Beat Schaefer,Annamaria Buccoliero,Elena Lazzeri,Paola Romagnani

doi:10.1016/j.stemcr.2015.07.003

Abstract

SummaryPodocyte loss is a general mechanism of glomerular dysfunction that initiates and drives the progression of chronic kidney disease, which affects 10% of the world population. Here, we evaluate whether the regenerative response to podocyte injury influences chronic kidney disease outcome. In models of focal segmental glomerulosclerosis performed in inducible transgenic mice where podocytes are tagged, remission or progression of disease was determined by the amount of regenerated podocytes. When the same model was established in inducible transgenic mice where renal progenitors are tagged, the disease remitted if renal progenitors successfully differentiated into podocytes, while it persisted if differentiation was ineffective, resulting in glomerulosclerosis. Treatment with BIO, a GSK3s inhibitor, significantly increased disease remission by enhancing renal progenitor sensitivity to the differentiation effect of endogenous retinoic acid. These results establish renal progenitors as critical determinants of glomerular disease outcome and a pharmacological enhancement of their differentiation as a possible therapeutic strategy.

Highlights

Chronic kidney diseases (CKDs) affects 10% of the population and represent a major global health burden (Eckardt et al, 2013)
We evaluate whether the regenerative response to podocyte injury influences chronic kidney disease outcome
In models of focal segmental glomerulosclerosis performed in inducible transgenic mice where podocytes are tagged, remission or progression of disease was determined by the amount of regenerated podocytes

Summary

Introduction

Chronic kidney diseases (CKDs) affects 10% of the population and represent a major global health burden (Eckardt et al, 2013). The number of patients with end-stage renal disease (ESRD) receiving renal replacement therapy is estimated at more than 1.4 million, with an annual growth rate of 8% (Schieppati and Remuzzi, 2005). ESRD represents only the tip of the iceberg; even early-stage CKD is associated with increased prevalence of numerous disorders and an increased risk of death. The course of CKD can be extremely variable. Even if pathophysiologic mechanisms of CKD progression are shared and independent of etiology, the reasons for this extreme outcome variability, even in patients affected by the same disorder, remain mostly unknown

Results

Discussion

Conclusion