Protective Effect and Possible Mechanisms of Artemisinin and Its Derivatives for Diabetic Nephropathy: A Systematic Review and Meta-Analysis in Animal Models

Abstract

Background. Artemisinin and its derivatives have potential antidiabetic effects. There is no evaluation of reported studies in the literature on the treatment of diabetic nephropathy (DN), one of the commonest diabetic microangiopathies, with artemisinins. Here, we aimed to evaluate preclinical evidence for the efficacy and possible mechanisms of artemisinins in reducing diabetic renal injury. Methods. We conducted an electronic literature search in fourteen databases from their inception to November 2021. All animal studies assessing the efficacy and safety of artemisinins in DN were included, regardless of publication or language. Overall, 178 articles were screened according to predefined inclusion and exclusion criteria. Finally, 18 eligible articles were included in this systematic review. The SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool was used to assess the risk of bias in the included studies. The primary outcomes were kidney function, proteinuria, and renal pathology. Secondary endpoints included changes in fasting plasma glucose (FPG) levels, body weight, and relevant mechanisms. Results. Of the 18 included articles involving 418 animal models of DN, 1, 2, 6, and 9 used dihydroartemisinin, artemether, artesunate, and artemisinin, respectively. Overall, artemisinins reduced indicators of renal function, including blood urea nitrogen ( $P<0.00001$ ), serum creatinine ( $P<0.00001$ ), and kidney index ( $P=0.0001$ ) compared with control group treatment. Measurements of proteinuria ( $P<0.00001$ ), microalbuminuria ( $P<0.05$ ), and protein excretion ( $P=0.0002$ ) suggested that treatment with artemisinins reduced protein loss in animals with DN. Artemisinins may lower blood glucose levels ( $P=0.01$ ), but there is a risk of weight gain ( $P<0.00001$ ). Possible mechanisms of action of artemisinins include delaying renal fibrosis, reducing oxidative stress, and exerting antiapoptotic and anti-inflammatory effects. Conclusion. Available evidence suggests that artemisinins may be protective against renal injury secondary to diabetes in preclinical studies; however, high-quality and long-term trials are needed to reliably determine the balance of benefits and harms.