Signaling pathways predisposing to chronic kidney disease progression
Mohamad Zaidan, … , Marco Pontoglio, Fabiola Terzi
Mohamad Zaidan, … , Marco Pontoglio, Fabiola Terzi
Published May 7, 2020
Citation Information: JCI Insight. 2020;5(9):e126183. https://doi.org/10.1172/jci.insight.126183.
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Research Article Nephrology

Signaling pathways predisposing to chronic kidney disease progression

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.

Authors

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

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Figure 1

Nephron reduction leads to 2 waves of cell proliferation in sensitive FVB mice.

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Nephron reduction leads to 2 waves of cell proliferation in sensitive FV...
(A) Representative cortical sections from FVB and B6 mice 2, 28, and 56 days after sham operation (Sh) or subtotal nephrectomy (Nx) stained with periodic acid-Schiff (original magnification, ×200; n = 4–6 and 10–12 for Sh and Nx, respectively, in each strain at each time point). (B) Representative images of Ki-67 immunostaining in B6 and FVB mice 2, 28, and 56 days after Nx and quantification of tubular cell proliferation index (original magnification, ×400; n = 4 Nx mice at least in each strain at each time point). Data are shown as mean ± SEM. Mann-Whitney U test. NxFVB versus NxB6 mice: #P < 0.05. (C) Time course analysis of kidney-to-body weight ratio in B6 and FVB mice 2, 28, and 56 days after Sh or Nx (n = 4–6 and 9–12 for Sh and Nx, respectively, in each strain at each time point). Data are shown as mean ± SEM. ANOVA was followed by the Tukey-Kramer test. Nx versus Sh mice: *P < 0.05; ***P < 0.001. FVB versus B6 mice: ###P < 0.001. (D) Tubular cells proliferation index by nephron segment in FVB and B6 mice 2, 28, and 56 days after Nx (n = 4 Nx mice in each strain at each time point) using coimmunostaining of Ki-67 and specific tubular markers: lotus tetragonolobus lectin (LTL) for proximal tubules, Tamm-Horsfall (TH) for the ascending Henle loop and distal convoluted tubules, and dolichos biflorus agglutinin (DBA) for collecting tubules. Data are shown as mean ± SEM. Mann-Whitney U test. NxFVB versus NxB6: #P < 0.05.