Exploring the Effect of Dapagliflozin on Alcoholic Kidney Injury and Renal Interstitial Fibrosis in Rats Based on TIMP-1/MMP-24 Pathway

Abstract

Objective. To establish a rat model of alcoholic kidney injury and detect the expression of TIMP-1/MMP-24 in the kidneys of rats with alcoholic kidney injury at the molecular pathological level, so as to explore the mechanism of alcohol abuse leading to kidney injury and renal interstitial fibrosis as well as the alleviation of alcohol-induced kidney injury and inhibition of renal interstitial fibrosis by dapagliflozin. Methods. 48 male rats were randomly divided into 4 groups: control group, alcohol group, alcohol + dapagliflozin group, and alcohol + losartan group, each with 12 rats. Different drugs were administered by gavage for modeling and treatment. Six days later, the rats were sacrificed, blood was collected from the heart to separate the serum, and the blood creatinine (Scr) and urea nitrogen (BUN) contents were detected biochemically. After blood collection, the kidney tissue was taken and fixed in10% neutral formalin. The expression of renal tissue inflammatory factors (CRP, IL-6, and TNF-α) and renal fibrosis indexes (LN, HA, and TGF-β1) were detected; MMP-24 and TIMP-1 in the kidney tissue of rats in different treatment groups were detected, and Smad3 expression was also detected. Results. After treatment, the general condition of the alcohol + dapagliflozin group and the alcohol + losartan group improved to different degrees. The weight first decreased and then gradually increased over time. There was no statistical difference in the weight change between the two groups; Compared with the control group, the Scr level, BUN content, renal index, inflammatory factors, and renal fibrosis indexes in the alcohol group were significantly increased ( P < 0.05 ); after 6 weeks of treatment, in the alcohol + dapagliflozin group and alcohol + losartan group, Scr level, BUN content, kidney index, inflammatory factors, and renal fibrosis indexes were significantly decreased ( P < 0.05 ); the expression of MMP-24 in the kidney tissue of the control group was upregulated, and the expression of TIMP-1 and Smad3 was downregulated; MMP-24 expression was downregulated, and TIMP-1 and Smad3 expression was significantly upregulated ( P < 0.05 ) in the rats of the alcohol group. After dapagliflozin and losartan treatment, MMP-24 expression gradually increased and TIMP-1 and Smad3 expression gradually decreased ( P < 0.05 ). Conclusion. Long-term large-scale alcohol intake can cause kidney tissue damage and fibrotic lesions. The expression of fibrotic cytokines such as TIMP-1 and Smad3 will increase, and the expression of MMP-24 will be decreased. However, dapagliflozin and losartan have certain therapeutic effects on the abovementioned lesions. The mechanism may be downregulating TIMP-1 and Smad3 and upregulating the expression of MMP-24 and other cytokines in the kidney.

Molecular Mechanisms and Risk Factors Related to the Pathogenesis of Peyronie’s Disease

“…A previous case–control study found that alcohol consumption was more frequent in PD cases as compared with a control group, although there was no difference related to the duration of alcohol consumption or types of beverages consumed [ 197 ]. Rat studies have also shown that long-term heavy alcohol consumption increases the expression of fibrotic cytokines such as TIMP-1 and SMAD3, leading to kidney tissue fibrosis [ 182 ]. Additionally, a study that investigated the early effects of alcohol intoxication on liver fibrosis in adolescents reported significantly elevated serum MMP-9 and TIMP-1 concentrations during intoxication [ 183 ].…”

Dapagliflozin alleviates renal fibrosis in a mouse model of adenine-induced renal injury by inhibiting TGF-β1/MAPK mediated mitochondrial damage

“…This is partly due to the lack of effective drugs. DN as an important cause of CKD, and some drugs treated with diabetes like SGLT2 inhibitors have shown renal protective effects ( Sharma et al, 2017 ; Kelly et al, 2019 ), as a typical drug of SGLT2 inhibitors, dapagliflozin’s renal protective effects on CKD have been demonstrated in patients with and without diabetes ( Kurata and Nangaku, 2022 ) , and it has also displayed antirenal fibrosis activities in animal models induced by unilateral ureter obstruction and alcohol damage ( Wu et al, 2021 ; Xuan et al, 2021 ; Liu et al, 2022 ). In this study, we extended this model to the setting of renal fibrosis induced by a 0.2% adenine diet.…”

“…Due to its protective effect in the kidneys of patients with non-diabetic chronic kidney disease, research into the use of dapagliflozin to treat renal fibrosis is underway. Studies have shown that dapagliflozin can reduce renal fibrosis in alcohol-induced kidney injury and unilateral ureteral obstruction (UUO) animal models ( Wu et al, 2021 ; Xuan et al, 2021 ; Liu et al, 2022 ).…”

Retracted: Exploring the Effect of Dapagliflozin on Alcoholic Kidney Injury and Renal Interstitial Fibrosis in Rats Based on TIMP‐1/MMP‐24 Pathway

“…Tis article has been retracted by Hindawi following an investigation undertaken by the publisher [1]. Tis investigation has uncovered evidence of one or more of the following indicators of systematic manipulation of the publication process:…”

“…This article has been retracted by Hindawi following an investigation undertaken by the publisher [ 1 ]. This investigation has uncovered evidence of one or more of the following indicators of systematic manipulation of the publication process: Discrepancies in scope Discrepancies in the description of the research reported Discrepancies between the availability of data and the research described Inappropriate citations Incoherent, meaningless and/or irrelevant content included in the article Peer-review manipulation …”