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

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