Role of HIF-1α and MORG1 in sepsis induced renal injury
Acronym: HIFMORG
Principal Investigators:
Claudia Schindler, Katrin Schindler
Scientific Advisors:
Prof. Dr. Gunter Wolf, MHBA
Tzvetanka Bondeva
Research Area: D Sepsis related
Organ Failure
Project Number: D1.3
Duration: 01.08.2010 - 31.07.2013
Module: PhD Fellowhip
The Problem
Clinical studies demonstrated that sepsis is associated with a high coincidence of an acute renal failure. Moreover, a pre-existing kidney disease is a major risk for an acute kidney injury. In this context, the project aims to gain more insights into the mechanisms of kidney dysfunction and whether Morg1 down-regulation or prolyl hydroxylases (PHDs) inhibition could reduce the severity of renal injury in sepsis via up-regulation of HIF-1α.
Results so far
The complex function of Morg1, HIF-1α and PHD3 in sepsis was studied by two mouse sepsis models CLP (cecal ligation and punture) and PCI (peritoneal contamination and infection) or LPS treatment in wild type (WT) (C57/Bl6) mice, Morg1 heterozygous (Morg1 HZ) mice and WT mice treated with PHD-Inhibitor (PHD-I) prior sepsis induction or LPS injection. The kidney damage after sepsis induction, or LPS injections was evaluated via analysis of the renal retention markers NGAL (neutrophil gelatinase-associated lipocalin) in blood plasma or urinary ACR. The alterations of NGAL values in blood plasma after 24 h in the experimental animals were significantly elevated in all models and a protective effect of PHD-I treatment or Morg1 HZ mice was not detected. On the other hand, analysis of the urinary ACR (albumin-creatinine ratio), another marker used to analyze the kidney function, showed no significant changes between the controls and treated mice in all models. This observation demonstrates the importance of the functional assays used to evaluate the kidney function in sepsis and its implications. The renal damage was also investigated via PAS-staining on kidney sections. Morg1 HZ and PHD-I pre-treated mice showed less damage of the kidney tissue upon sepsis induction, characterized with a reduced dilation and vacuolisation of proximal tubular cells compare with the WT septic mice. Especially in CLP-sepsis models the differences in the PAS-staining were obvious. Detection of the activated Caspase-3 by IHC on kidney sections demonstrated as well that in kidneys of Morg1 HZ and PHD-I treated mice were observed less apoptotic cells after sepsis induction or LPS injection then in WT animals.
IHC analysis found that the protein levels of HIF-1α, HIF-2α and TNFα were higher in Morg1 HZ sham and PHD-I treated sham mice compare with the WT sham animals. Furthermore, in CLP but not in PCI septic mice the protein levels of HIF-1α, HIF-2α, and TNFα were as well up-regulated in treated Morg1 HZ mice and PHD-I pre-treated mice relative to WT. Survival studies unveiled that neither Morg1 HZ mice, nor PHD-I treated mice were protected in CLP or PCI sepsis models compare with the WT septic mice. Nevertheless, the clinical severity score analysis (CSS) demonstrated that there was not a significant difference between the Morg1 HZ controls (sham operated) mice and CLP treated mice 24 h post CLP sepsis induction. Similarly, in PCI sepsis model, both Morg1 HZ and PHD-I treated mice demonstrated better conditions after 24 h PCI treatment, relatively to the WT mice. The LPS mouse model was in general less severe then CLP and PCI- sepsis models, and PHD-I treated mice showed lower CSS after 24 h LPS exposure in comparison to WT and Morg1 HZ animals. Our data demonstrate that the stimulation of HIF-1α has a nephroprotective function in the above experimental models.
Contact
Tel. +49 (0)3641 - 9 32 43 01
Universitätsklinikum Jena
Klinik für Innere Medizin III
Erlanger Allee 101
07747 Jena