Abstract
We analyzed the effects of acute ischemia-reperfusion (KIR) injury on the status of kidney function and architecture in dipeptidyl peptidase4-difficient (DPP4D) rats and the effect of remote small bowel ischemia-reperfusion (BIR) preconditioning. DPP4-deficient (DPP4D) and normal Fischer344 (F344) rats were divided into 6 groups: (1) sham-F344, (2) sham-DPP4D, (3) KIR-F344 (4) KIR-DPP4D, (5) DPP4D-KIR-extendin-9-39 and (6) BIR-KIR-F344. Blood creatinine and urea nitrogen levels and the urinary protein-to-creatinine ratio was higher in KIR-F344 rats than BIR-KIR-F344 or KIR-DPP4D rats 72 h after acute KIR. Conversely, the circulating glucagon-like peptide 1 (GLP-1) levels were higher in BIR-KIR-F344 and KIR-DPP4D than KIR-F344 rats after acute KIR. KIR-F344 rats showed greater inflammation, oxidative stress, apoptosis, DNA damage and kidney injury than other rat groups. Damage to the kidney architecture in KIR-F344 rats was greater than in BIR-KIR-F344 or KIR-DPP4D rats. Expression of antioxidant proteins and GLP-1 receptor was higher in kidneys from KIR-DPP4D and BIR-KIR-F344 than KIR-F344 rats, which suggests better intrinsic responses. We therefore suggest that elevated circulating GLP-1 levels due to DPP4 deficiency and BIR preconditioning protect kidney function and architecture during acute IR injury.
Highlights
Despite novel drugs and improvements in critical care including renal replacement therapy, the outcomes for critically ill acute kidney injury (AKI) patients remains poor and its incidence during hospitalization keeps increasing [1,2,3,4,5,6]
72 h after acute kidney ischemia-reperfusion (KIR), blood creatinine and blood urea nitrogen (BUN) levels that indicate renal dysfunction, and the urine protein to creatinine ratio that indicate glomerular damage were lowest in the sham control (SC)-F344 and SC-dipeptidyl peptidase4-difficient (DPP4D) rats and gradually increased in bowel ischemia-reperfusion (BIR)-KIR-F344, KIR-DPP4D, DPP4D-KIRexendin-9-39 rats and were highest in KIR-F344 rats (Figure 1)
The higher circulating glucagon-like peptide 1 (GLP-1) levels on day 3 after acute KIR in the KIR-DPP4D + Ex4-9-39 rats compared to KIR-BIR-F344 rats suggested enhanced intrinsic response to the occupied GLP-1 receptor (GLP-1R) in kidney parenchyma elicited by Ex4-9-39 (Figure 2)
Summary
Despite novel drugs and improvements in critical care including renal replacement therapy, the outcomes for critically ill acute kidney injury (AKI) patients remains poor and its incidence during hospitalization keeps increasing [1,2,3,4,5,6]. Acute kidney ischemia-reperfusion (KIR) that causes AKI is frequently observed during contrast-media induced nephropathy [5], post-resuscitation shock [7], kidney transplantation [8] and chemical or drug toxicity. These result in acute tubular-epithelial damage [9, 10], loss of tubular microvasculature [11] and inflammation and leukocyte infiltration [8,9,10, 12]. Increased circulating levels of GLP-1 may protect the kidney from acute IR injury
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