FGF/FGFR2 Protects against Tubular Cell Death and Acute Kidney Injury Involving Erk1/2 Signaling Activation.

BACKGROUND: Fibroblast growth factors (FGFs) are heparin-binding proteins involved in a variety of biological processes, and part of them may act through binding with cell membrane receptor FGFR2. OBJECTIVES: To clarify the role and mechanisms of FGFR2 signaling in tubular cell survival and acute kidney injury (AKI). METHOD: In this study, kidney ischemia/reperfusion (IR) or cisplatin injection was used to induce AKI in mice. RESULTS: In the kidneys after IR or cisplatin injection, the expression of FGFs and Erk1/2 phosphorylation were elevated. To investigate the role of FGFs in tubular cell survival and AKI, a mouse model with tubular cell specific FGFR2 gene disruption was generated. The knockouts were born normal. At 2 months of age, about one-third of the knockouts developed mild hydronephrosis. Ablation of FGFR2 in tubular cells aggravated acute kidney dysfunction as well as tubular cell apoptosis induced by IR or cisplatin. In addition, Erk1/2 phosphorylation was less in the knockout kidneys than in control littermates at day 1 after cisplatin injection. In cultured NRK-52E cells, recombinant FGF2 protein induced Erk1/2 phosphorylation and inhibited cisplatin-induced cell death. PD98059 abolished Erk1/2 phosphorylation and partly reversed the protective effect of FGF2 on cisplatin-induced cell death. CONCLUSIONS: This study indicates that FGF/FGFR2 signaling plays an important role in protecting against tubular cell death and AKI, which is partly through stimulating Erk1/2 activation.

Fibroblast mTOR/PPARγ/HGF axis protects against tubular cell death and acute kidney injury.

Kidney fibroblasts play a crucial role in dictating tubular cell fate and the outcome of acute kidney injury (AKI). The underlying mechanisms remain to be determined. Here, we found that mTOR signaling was activated in fibroblasts from mouse kidneys with ischemia/reperfusion injury (IRI). Ablation of fibroblast Rheb or Rictor promoted, while ablation of fibroblast Tsc1 protected against tubular cell death and IRI in mice. In tubular cells cultured with conditioned media (CM) from Rheb-/- or Rictor-/- fibroblasts, less hepatocyte growth factor (HGF) receptor c-met signaling activation or staurosporine-induced cell apoptosis was observed. While CM from Tsc1-/- fibroblasts promoted tubular cell c-met signaling activation and inhibited staurosporine-induced cell apoptosis. In kidney fibroblasts, blocking mTOR signaling downregulated the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and HGF. Downregulating fibroblast HGF expression or blocking tubular cell c-met signaling facilitated tubular cell apoptosis. Notably, renal PPARγ and HGF expression was less in mice with fibroblast Rheb or Rictor ablation, but more in mice with fibroblast Tsc1 ablation than their littermate controls, respectively. Together, these data suggest that mTOR signaling activation in kidney fibroblasts protects against tubular cell death and dictates the outcome of AKI through stimulating PPARγ and HGF expression.

The signaling protein Wnt5a promotes TGFß1-mediated macrophage polarization and kidney fibrosis by inducing the transcriptional regulators Yap/Taz.

M2 macrophage polarization is known to underlie kidney fibrosis. We previously reported that most of the members of the Wnt family of signaling proteins are induced in fibrotic kidneys. Dysregulation of the signaling protein Wnt5a is associated with fibrosis, but little is known about the role of Wnt5a in regulating M2 macrophage activation that results in kidney fibrosis. Here, using murine Raw 264.7 cells and bone marrow-derived macrophages, we found that Wnt5a enhanced transforming growth factor ß1 (TGFß1)-induced macrophage M2 polarization as well as expression of the transcriptional regulators Yes-associated protein (Yap)/transcriptional coactivator with PDZ-binding motif (Taz). Verteporfin blockade of Yap/Taz inhibited both Wnt5a- and TGFß1-induced macrophage M2 polarization. In mouse models of kidney fibrosis, shRNA-mediated knockdown of Wnt5a expression diminished kidney fibrosis, macrophage Yap/Taz expression, and M2 polarization. Moreover, genetic ablation of Taz in macrophages attenuated kidney fibrosis and macrophage M2 polarization in mice. Collectively, these results indicate that Wnt5a promotes kidney fibrosis by stimulating Yap/Taz-mediated macrophage M2 polarization.

[A bird's eye view of the algorithms and software packages for reconstructing phylogenetic trees].

The prototype phylogenetic tree, i.e., evolutionary "tree" or "tree of life", was first conceived by Charles Darwin in his seminal book "The Origin of Species", and its reconstructions have been approached by generations of biologists ever since. In this article, we briefly reviewed the major algorithms and software packages for reconstructing phylogenetic trees. Specifically we discuss four categories of phylogeny algorithms including distance-matrix, maximum parsimony, maximum likelihood, and Bayesian framework, as well as software packages (PHYLIP, MEGA, MrBayes) based on them.

[Treatments of geriatric femoral intertrochanteric fractures].

OBJECTIVE: To investigate the treatment method of senile patients with femoral intertrochanteric fractures and its clinical outcomes. METHODS: From January 2005 to December 2007, 192 senile patients with femoral intertrochanteric fractures were treated, including 85 males and 107 females aged 65-92 years old (average 75 years old). The injury was caused by fall on walking in 106 cases, fall when riding a bicycle in 55 cases, and traffic accidents in 31 cases. According to Evans classification, there were 12 cases of type I A, 43 cases of type I B, 29 cases of type II, 24 cases of type III A, 23 cases of type III B, 26 cases of type IV, and 35 cases of type V. One hundred and fifty patients were associated with cardio-cerebrovascular diseases, 120 patients were complicated with chronicle hypertension, 90 cases were associated with bronchitis, and 75 cases were complicated with diabetes. The time from injury to hospital admission was 1 hour to 14 days. Among those patients, 108 were treated with conservative treatment, 68 received dynamic hip screw (DHS) fixation, and 16 underwent proximal femoral Gamma nail fixation. RESULTS: All the patients were followed up for 12-36 months (average 18 months). The fracture all reached bone union without occurrence of nonunion and delayed union. Patients could take care of themselves, and there were no occurrences of serious pains and dysfunctions. The therapeutic effect was satisfactory. The conservative treatment group: the average hospital stay length was 48 days; the average bone healing time was 14 weeks; 23 cases had different degrees of coxa adducts; Harris score system was adopted to evaluate hip joint function, 45 cases were graded as excellent, 31 as good, 10 as fair, and 22 as poor, and the excellent and good rate was 70.4%. DHS internal fixation group: the average operation time was 60 minutes; the average bleeding volume during operation was 200 mL, the average hospital stay length was 24 days; the average bone healing time after operation was 12 weeks; Harris score system was adopted to evaluate the injured hip joint function, 38 cases were graded as excellent, 21 as good, 8 as fair, and 1 as poor, and the excellent and good rate was 86.8%. Gamma nail fixation group: the average operation time was 70 minutes; the average bleeding volume during operation was 200 mL, the average hospital stay length was 14 days; the average bone healing time after operation was 12 weeks; Harris score system was adopted to evaluate the injured hip joint function, 11 cases were graded as excellent, 4 as good, 1 as fair, and the excellent and good rate was 93.8%. CONCLUSION: For geriatric femoral intertrochanteric fractures, operative treatment should be performed, the preoperative preparation should be sufficient, and individual-oriented treatment method should be selected on the basis of physical conditions of patients and the types of fractures.