TNF-α mediates increased susceptibility to ischemic AKI in diabetes

Guofeng Gao, Binzhi Zhang, Ganesan Ramesh, Daniel Betterly, Raghu K. Tadagavadi, Weiwei Wang, W. Brian Reeves

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Diabetes is a risk factor for the development of acute kidney injury (AKI) in humans and rodents. However, the mechanistic basis for this observation is unknown. The present studies evaluated the role of inflammation and TNF-α in ischemic AKI in a model of type 2 diabetes mellitus (DM). Diabetic (db/db) and nondiabetic (db/+) littermates were subjected to 20 min of bilateral renal ischemia. The nondiabetic mice developed only mild and transient renal dysfunction. In contrast, the equivalent ischemic insult provoked severe and sustained renal dysfunction in the db/db mice. The expression of TNF-α and Toll-like receptor 4 (TLR4) mRNA was measured in the kidneys of diabetic mice before and after renal ischemia; db/db mice exhibited greater increases in TNF-α and TLR4 mRNA expression following ischemia than did db/+. In addition, urinary excretion of TNF-α after ischemia was higher in db/db mice than in db/+ mice. To determine the possible role of TNF-α in mediating the enhanced susceptibility of diabetic mice to ischemic injury, db/db mice were injected with either a neutralizing anti-mouse TNF-α antibody or nonimmune globulin and then subjected to 20 min of bilateral renal ischemia. Treatment of the db/db mice with the TNF-α antibody provided significant protection against the ischemic injury. These data support the view that diabetes increases the susceptibility to ischemia-induced renal dysfunction. This increased susceptibility derives from a heightened inflammatory response involving TNF-α and perhaps TLR4 signaling.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Renal Physiology
Volume304
Issue number5
DOIs
StatePublished - Mar 11 2013

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Acute Kidney Injury
Ischemia
Kidney
Toll-Like Receptor 4
Messenger RNA
Antibodies
Globulins
Wounds and Injuries
Type 2 Diabetes Mellitus
Rodentia
Inflammation

Keywords

  • Acute kidney injury
  • Diabetes
  • Ischemia
  • TNF

ASJC Scopus subject areas

  • Physiology
  • Urology

Cite this

Gao, G., Zhang, B., Ramesh, G., Betterly, D., Tadagavadi, R. K., Wang, W., & Brian Reeves, W. (2013). TNF-α mediates increased susceptibility to ischemic AKI in diabetes. American Journal of Physiology - Renal Physiology, 304(5). https://doi.org/10.1152/ajprenal.00533.2012

TNF-α mediates increased susceptibility to ischemic AKI in diabetes. / Gao, Guofeng; Zhang, Binzhi; Ramesh, Ganesan; Betterly, Daniel; Tadagavadi, Raghu K.; Wang, Weiwei; Brian Reeves, W.

In: American Journal of Physiology - Renal Physiology, Vol. 304, No. 5, 11.03.2013.

Research output: Contribution to journalArticle

Gao, G, Zhang, B, Ramesh, G, Betterly, D, Tadagavadi, RK, Wang, W & Brian Reeves, W 2013, 'TNF-α mediates increased susceptibility to ischemic AKI in diabetes', American Journal of Physiology - Renal Physiology, vol. 304, no. 5. https://doi.org/10.1152/ajprenal.00533.2012
Gao, Guofeng ; Zhang, Binzhi ; Ramesh, Ganesan ; Betterly, Daniel ; Tadagavadi, Raghu K. ; Wang, Weiwei ; Brian Reeves, W. / TNF-α mediates increased susceptibility to ischemic AKI in diabetes. In: American Journal of Physiology - Renal Physiology. 2013 ; Vol. 304, No. 5.
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