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
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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 9

Early IFN activation induces glomerulosclerosis after nephron reduction in resistant B6 mice.

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Early IFN activation induces glomerulosclerosis after nephron reduction ...
(A) Experimental protocol used for IFN response induction in initially resistant B6 mice. Mice were injected intraperitoneally with poly(I:C) or placebo (saline buffer) every 2 days during the week after the first nephrectomy (Nx, n = 12 per group) or sham operation (Sh, n = 6 per group). The first Nx corresponded to the excision of the 2 poles of the left kidney. The contralateral (right) kidney (second Nx) was removed 1 week after the first surgery and mice were sacrificed 16 weeks after the second Nx. (B) Renal mRNA expression of Irf7 and SiglecH in placebo- and poly(I:C)–treated NxB6 mice at the time of the second Nx surgery (n = 11 per group). Data are shown as mean ± SEM. Mann-Whitney test. Poly(I:C)– versus placebo-treated mice: ###P < 0.001. (C) Representative images (left, periodic acid-Schiff staining; original magnification, ×400) and quantification (right) of glomerular lesions from ShB6 and NxB6 mice injected with placebo or poly(I:C) for 1 week and sacrificed 16 weeks afterward (n = 6 and 10–11 for Sh and Nx, respectively, in each group). Data are shown as mean ± SEM. ANOVA was followed by the Tukey-Kramer test. Nx versus Sh mice: ***P < 0.001. Poly(I:C)– versus placebo-treated mice: ##P < 0.01. (D) Representative urine Coomassie staining and (E) albumin-to-creatinine ratio in ShB6 and NxB6 mice injected with placebo or poly(I:C) for 1 week and sacrificed 16 weeks afterward (n = 6 and 10–11 for Sh and Nx, respectively, in each group). BSA served as the positive control. Data are shown as mean ± SEM. ANOVA was followed by the Tukey-Kramer test. Nx versus Sh mice: **P < 0.01. Poly(I:C)– versus placebo-treated mice: #P < 0.05.