Protection of glucagon-like peptide-1 in cisplatin-induced renal injury elucidates gut-kidney connection.

Abstract

Accumulating evidence of the beyond-glucose lowering effects of a gut-released hormone, glucagon-like peptide-1 (GLP-1), has been reported in the context of remote organ connections of the cardiovascular system. Specifically, GLP-1 appears to prevent apoptosis, and inhibition of dipeptidyl peptidase-4 (DPP-4), which cleaves GLP-1, is renoprotective in rodent ischemia-reperfusion injury models. Whether this renoprotection involves enhanced GLP-1 signaling is unclear, however, because DPP-4 cleaves other molecules as well. Thus, we investigated whether modulation of GLP-1 signaling attenuates cisplatin (CP)-induced AKI. Mice injected with 15 mg/kg CP had increased BUN and serum creatinine and CP caused remarkable pathologic renal injury, including tubular necrosis. Apoptosis was also detected in the tubular epithelial cells of CP-treated mice using immunoassays for single-stranded DNA and activated caspase-3. Treatment with a DPP-4 inhibitor, alogliptin (AG), significantly reduced CP-induced renal injury and reduced the renal mRNA expression ratios of Bax/Bcl-2 and Bim/Bcl-2. AG treatment increased the blood levels of GLP-1, but reversed the CP-induced increase in the levels of other DPP-4 substrates such as stromal cell-derived factor-1 and neuropeptide Y. Furthermore, the GLP-1 receptor agonist exendin-4 reduced CP-induced renal injury and apoptosis, and suppression of renal GLP-1 receptor expression in vivo by small interfering RNA reversed the renoprotective effects of AG. These data suggest that enhancing GLP-1 signaling ameliorates CP-induced AKI via antiapoptotic effects and that this gut-kidney axis could be a new therapeutic target in AKI.

• Authors: Daisuke Katagiri, Yoshifumi Hamasaki, Kent Doi, Koji Okamoto, Kousuke Negishi, Masaomi Nangaku, Eisei Noiri
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 24 Issue 12 Pg. 2034-43 (Dec 2013) ISSN: 1533-3450 [Electronic] United States
• PMID: 24092928 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Dipeptidyl-Peptidase IV Inhibitors
• Glp1r protein, mouse
• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents
• Peptides
• Piperidines
• RNA, Small Interfering
• Receptors, Glucagon
• Venoms
• Uracil
• Glucagon-Like Peptide 1
• Exenatide
• alogliptin
• Cisplatin

Topics

• Acute Kidney Injury (chemically induced, drug therapy, metabolism)
• Animals
• Antineoplastic Agents (toxicity)
• Apoptosis (drug effects, physiology)
• Cisplatin (toxicity)
• Dipeptidyl-Peptidase IV Inhibitors (pharmacology)
• Exenatide
• Glucagon-Like Peptide 1 (metabolism)
• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents (pharmacology)
• Intestinal Mucosa (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Oxidative Stress (drug effects, physiology)
• Peptides (pharmacology)
• Piperidines (pharmacology)
• RNA, Small Interfering (pharmacology)
• Receptors, Glucagon (agonists, genetics, metabolism)
• Reperfusion Injury (chemically induced, drug therapy, metabolism)
• Uracil (analogs & derivatives, pharmacology)
• Venoms (pharmacology)