P0545DPP-4 INHIBITOR ATTENUATED RENAL VASOCONSTRICTION FOLLOWING ISCHEMIA-REPERFUSION INJURY IN CIRRHOTIC RATS
Authors: CHUANG CHIAO-LIN , Huang Hui-Chun 
Published: June 2020

Abstract

Background and Aims
Cirrhotic patients may develop gastroesophageal varices to cope with portal hypertension. Annual risk of variceal bleeding among small and large varices is 5% and 15%, respectively. Bleeding from varices is a medical emergency and is associated with a high morbidity and mortality. In those who survive the initial bleeding event, the risks of further bleeding and other serious complications remain high, such as hypotension and ischemia-reperfusion injury. Ischemia-reperfusion injury is a leading cause of acute kidney injury. In patients with advanced liver cirrhosis, variceal bleeding associated hypotension and ischemia-reperfusion injury may activated endogenous vasoconstrictors, leading to severe renal vasoconstriction and subsequent renal failure (so called hepatorenal syndrome). There was not effective treatment yet.
Dipeptidyl peptidase-4 (DPP-4) inhibitors, a new class of oral hypoglycemic agents, have shown potential pleiotropic effects, such as anti-inflammatory and anti-oxidant properties. Previous studies reported that inhibition of DPP-4 could attenuate the development of ischemia-reperfusion injury in kidney. Cumulated evidences indicates that DPP-4 inhibitors could attenuate the endothelin-1 induced contraction and increase endothelial-dependent vasodilation related to activation of endothelial nitric oxide synthase and increased production of nitric oxide. In addition, DPP-4 inhibitors may suppress inflammation and fibrosis in the kidneys independently of glycemic control. The aim of this study is to delineate the effect of DPP-4 inhibitors in renal vascular reactivity of cirrhotic rats following ischemia-reperfusion injury.

Method
Male Sprague-Dawley rats weighing 240-270 g were used for experiments. Secondary biliary cirrhosis were created by common bile duct ligation (CBDL). Rats receiving sham surgery (SHAM) were used as the control group. Linagliptin (3 mg/kg/day) or distilled water (DW) was administered via oral gavage since the 1st day throughout the 28th day after surgery. On the 29th day, all rats were randomized to control group or ischemia-reperfusion injury. Bilateral renal pedicles of rats in the ischemia-reperfusion injury group were clamped for 45 minutes with microvascular clamps. Thereafter, the clamps were removed and reperfusion was allowed by visual control. After 60 minutes of reperfusion period, kidneys were perfused in situ via right renal artery for continuous monitoring of renal perfusion pressure using a non-recirculating system.

Results
There was no significant difference in mean arterial pressure, heart rate, and portal pressure between DW and DPP-4 inhibitor treated groups in both SHAM and CBDL rats. Ischemia-reperfusion injury enhanced renal vascular reactivity to endothelin-1 in both SHAM (p = 0.027) and CBDL (p = 0.016) rats, implying renal vasoconstriction. Compared with corresponding DW-treated rats, DPP-4 inhibitor treatment abrogated renal hyper-reactivity following ischemia-reperfusion injury in BDL rats (p = 0.038), but not in SHAM rats (p = 0.17).

Conclusion
We concluded that DPP-4 inhibitors may attenuate the development of renal vasoconstriction following ischemia-reperfusion injury in cirrhotic rats. The potentially mechanisms remained to be elucidated.