Signaling pathways predisposing to chronic kidney disease progression
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
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
View: Text | PDF
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

×

Figure 7

Different patterns of tubular cell death in sensitive and resistant strains after nephron reduction.

Options: View larger image (or click on image) Download as PowerPoint
Different patterns of tubular cell death in sensitive and resistant stra...
(A) Analysis of phospho–histone H2A.X (Ser139) expression by immunohistochemistry (left, original magnification, ×200, inset 2×; n = 4 mice per group in each strain) and Western blot (right) in FVB and B6 mice 2 days after sham operation (Sh) or subtotal nephrectomy (Nx) (n = 5–6 mice per group in each strain). Data are shown as mean ± SEM. ANOVA was followed by the Tukey-Kramer test. Nx versus Sh mice: **P < 0.01; ***P < 0.001. (B) Analysis of Ripk3 and Mlkl mRNA expression in FVB and B6 mice 2 days after Sh or Nx (n = 5–6 and 10 for Sh and Nx mice, respectively, in each strain). Data are shown as mean ± SEM. ANOVA was followed by the Tukey-Kramer test. Nx versus Sh mice: ***P < 0.001. FVB versus B6 mice: ###P < 0.001. (C) Representative images (left) and quantification (right) of TUNEL apoptosis assay in FVB and B6 mice 2 days after Nx (n = 8 mice per group). Data are shown as mean ± SEM. (D) Representative images (left) and quantification (right) of KIM1 expression in B6 and FVB mice 2 days after Sh or Nx (original magnification, ×200, inset 3×; n = 4 mice, 5 for Sh and Nx, respectively, in each strain). 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 < 0.05. (E) Kim1 mRNA expression in FVB and B6 mice 2 days after Sh or Nx (n = 5–6 and 10 for Sh and Nx, respectively, in each strain). Data are shown as mean ± SEM. ANOVA was followed by the Tukey-Kramer test. Nx versus Sh mice: ***P < 0.001. FVB versus B6 mice: ###P < 0.001.