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Endotoxin-induced renal inflammatory response. Oncostatin M as a major mediator of suppressed renin expression
H Baumann1, Y Wang, C D Richards
1Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. Heinz.Baumann@sc3101.med.buffalo.edu
Abstract:
The systemic response to endotoxin is characterized by hypotension and severe reductions in blood pressure, leading to cardiovascular collapse that can accompany septicemia. The renin/angiotensin system would normally be expected to respond to hypotensive challenge; however, inflammation appears to modify this response. This study identifies a strong acute phase response of the kidney that is characterized by enhanced expression of serum amyloid A, haptoglobin and tissue inhibitor for metalloproteinase-1 and a reduced expression of renin. Equivalent regulatory effects were observed for the immortalized As4.1 kidney cell line that models certain features of juxtaglomerular cells. Oncostatin M, a known endotoxin-responsive proinflammatory cytokine, proved to be an effective inhibitor of renin gene expression. Suppression by oncostatin M involves activated STAT5 and requires an inhibitory element in the renin promoter that functions separately from cell type-specific enhancer elements. The renal acute phase reaction, unlike the liver acute phase reaction, is more strongly dependent on locally produced inflammatory factors.
Insights
Endotoxin exposure triggers kidney inflammation, altering the renin-angiotensin system and reducing renin expression. This renal acute phase response relies more on local inflammatory factors than systemic ones.
Area of Science:
- Nephrology
- Immunology
- Cardiovascular Physiology
Background:
- Systemic endotoxin exposure causes hypotension and cardiovascular collapse, typical of septicemia.
- The renin-angiotensin system typically counteracts hypotension, but inflammation can disrupt this response.
Purpose of the Study:
- To investigate the kidney's response to endotoxin, focusing on the renin-angiotensin system.
- To elucidate the mechanisms underlying altered renin gene expression during inflammation.
Main Methods:
- Analysis of gene expression (serum amyloid A, haptoglobin, tissue inhibitor for metalloproteinase-1, renin) in kidney tissue and immortalized kidney cells (As4.1).
- Investigating the role of Oncostatin M (OSM) and its signaling pathway (STAT5) in regulating renin gene expression.
Main Results:
- Kidneys exhibit an acute phase response with increased expression of specific inflammatory markers and decreased renin expression.
- Oncostatin M effectively inhibits renin gene expression in kidney cells.
- OSM-induced renin suppression involves activated STAT5 and a distinct inhibitory element in the renin promoter.
Conclusions:
- The kidney displays a unique acute phase reaction to endotoxin, characterized by suppressed renin expression.
- Local inflammatory factors, particularly Oncostatin M, play a crucial role in modulating the renal acute phase response and renin regulation.