Egypt is the eighth-leading country in the prevalence of diabetes mellitus (DM). It was estimated that more than ten million adults would suffer from DM in Egypt in 2022. Diabetic nephropathy (DN) is one of the complications of DM, which can lead to end-stage renal disease (ESRD). There is limited information on the efficacy of pioglitazone and/or rosuvastatin in diabetic kidney diseases (DKD). In this study, 40 male rats were divided into two groups: the control group (8 rats) and the diabetic group (32 rats), in which rats were fed a high-fat diet (HFD) for 4 weeks and then injected intraperitoneally (IP) with streptozotocin (STZ). The diabetic group was then subdivided into four equal groups as follows: Group 1: diabetic non-treated; Group 2: diabetic + treated with pioglitazone orally at a dose of 10 mg/kg once daily for 4 weeks; Group 3: diabetic + treated with rosuvastatin orally at a dose of 10 mg/kg once daily for 4 weeks; and Group 4: diabetic + treated with pioglitazone and pioglitazone orally at a dose of 10 mg/kg for each of them once daily for 4 weeks. At the end of the experiment (8 weeks), blood samples were taken to study their effects on the diabetic kidney by evaluating kidney function tests. The left kidney was taken to detect the gene expression of inflammatory markers such as tumor necrosis factor-α (TNF-α) and interleukin (IL-1β), as well as CYP 2E1, and the right kidney was taken to detect histopathological changes in renal tissues.