Signaling pathways predisposing to chronic kidney disease progression.

Mohamad Zaidan,Serge Garbay,Laura Badi,Morgan Gallazzini,Pauline Barre,Jitao David Zhang,Marie-Claire Gubler,Marco Pontoglio,Fabiola Terzi,Martine Burtin,Gérard Friedlander,Thomas Blanc,Serena Germano,Clément Nguyen,Lucie Yammine,Florence Vasseur

doi:10.1172/jci.insight.126183

Abstract

The loss of functional nephrons after kidney injury triggers the compensatory growth of the remaining ones to allow functional adaptation. However, in some cases, these compensatory events activate signaling pathways that lead to pathological alterations and chronic kidney disease. Little is known about the identity of these pathways and how they lead to the development of renal lesions. Here, we combined mouse strains that differently react to nephron reduction with molecular and temporal genome-wide transcriptome studies to elucidate the molecular mechanisms involved in these events. We demonstrated that nephron reduction led to 2 waves of cell proliferation: the first one occurred during the compensatory growth regardless of the genetic background, whereas the second one occurred, after a quiescent phase, exclusively in the sensitive strain and accompanied the development of renal lesions. Similarly, clustering by coinertia analysis revealed the existence of 2 waves of gene expression. Interestingly, we identified type I interferon (IFN) response as an early (first-wave) and specific signature of the sensitive (FVB/N) mice. Activation of type I IFN response was associated with G1/S cell cycle arrest, which correlated with p21 nuclear translocation. Remarkably, the transient induction of type I IFN response by poly(I:C) injections during the compensatory growth resulted in renal lesions in otherwise-resistant C57BL6 mice. Collectively, these results suggest that the early molecular and cellular events occurring after nephron reduction determine the risk of developing late renal lesions and point to type I IFN response as a crucial event of the deterioration process.

Highlights

Chronic kidney disease (CKD), one of the major public health challenges of the 21st century, is characterized by the progressive decline of renal function to end-stage renal disease (ESRD) that may occur, irrespective of the cause of the renal damage, once a critical number of nephrons has been lost [1,2,3]
10% to 15% of adults suffer from CKD, and the incidence of ESRD increases by 6% to 8% per year [1, 2]
To better understand the nature of the events that lead to either the renal compensatory growth or the lesion development after nephron reduction, we first studied the temporal modifications of renal architecture and the pattern of tubular cell proliferation in the sensitive FVB/N and resistant C57BL6 mice at 2, 28, and 56 days after Nx

Summary

Introduction

Chronic kidney disease (CKD), one of the major public health challenges of the 21st century, is characterized by the progressive decline of renal function to end-stage renal disease (ESRD) that may occur, irrespective of the cause of the renal damage, once a critical number of nephrons has been lost [1,2,3]. 10% to 15% of adults suffer from CKD, and the incidence of ESRD increases by 6% to 8% per year [1, 2]. Because of the persistently poor outcome of ESRD, current clinical research efforts focus on preventive strategies to slow down the rate of CKD progression. Attempts to dissect the molecular basis of CKD have been facilitated by the development of several experimental animal models. Over the last 50 years, the study of this model has led to the discovery of critical pathways and, more importantly, to the design of therapeutic strategies to delay CKD progression, such as renin-angiotensin inhibitors [7, 8]

Methods

Results

Conclusion