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

Katagiri D, Hamasaki Y, Doi K, Okamoto K, Negishi K, Nangaku M, Noiri E
J Am Soc Nephrol. 2013 24 (12): 2034-43

PMID: 24092928 · PMCID: PMC3839550 · DOI:10.1681/ASN.2013020134

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.

MeSH Terms (22)

Acute Kidney Injury Animals Antineoplastic Agents Apoptosis Cisplatin Dipeptidyl-Peptidase IV Inhibitors Exenatide Glucagon-Like Peptide-1 Receptor Glucagon-Like Peptide 1 Hypoglycemic Agents Intestinal Mucosa Male Mice Mice, Inbred C57BL Oxidative Stress Peptides Piperidines Receptors, Glucagon Reperfusion Injury RNA, Small Interfering Uracil Venoms

Connections (1)

This publication is referenced by other Labnodes entities: