Chronic kidney disease (CKD) is considered one of the major public health problems associated with high prevalence, morbidity, and mortality. There is no definite cure for CKD, however studying its underlying mechanisms has provided more understanding of its pathophysiology, hence the development of new therapeutic approaches. Fructose consumption increased the risk of developing metabolic syndrome (MetS), dyslipidemia, diabetes, hyperuricemia, bone health, oxidative stress, hypertension, CVD and CKD. It have been shown that MetS is associated with the developing of kidney injury. The mechanism by which fructose ameliorates renal function is not fully known. This study was undertaken to investigate the therapeutic effect of dulaglutide, empagliflozine and pirfenidone on fructose-induced CKD and to elucidate the underlying mechanism particularly the contribution of GSK-3β, apoptotic signaling and fibrogenic pathways. High fructose feeding rats showed marked hyperglycemia, hyperinsulinema, increased HOMA-IR as a consequence as well as elevated serum creatinine, serum uric acid and (KIM-1) and suppression of renal podocin content as compared to normal control group. Significant elevation in total and phosphorylated glycogen synthase kinase 3 beta (GSK-3β) and pro-apoptotic proteins, Bax and cleaved caspase-3, with suppression of pro-survival protein, Bcl-2, which indicated the activation of renal apoptosis. Significant elevation in renal fibrotic markers as TGF- β1 and Smad3 were also recorded. The activation of EMT were also confirmed via reduction of E-cadherin and increase of vimentina and αSMA in the kidney of fructose-fed rats. These biochemical findings were further supported by the histological analysis which revealed mesangial expansion, inflammatory cellular infiltrations, glomerulosclerosis and tubulointerstitial fibrosis in renal tissue of fructose-fed rats. Treatment with empagliflozine, dulaglutide or the combined treatments markedly reduced the BGL, serum insulin and HOMA-IR. All treatments used significantly reduced the dyslipidemia, the serum creatinine, serum uric acid and the kidney injury markers and KIM-1.as well as elevated the renal podocin content. In addition to marked suppression of apoptotic markers, fibrotic markers and EMT pathway. Additionally, the histological examination showed marked reduction in mesangial expansion, inflammatory cellular infiltrations, glomerulosclerosis and tubulointerstitial fibrosis in renal tissue of treated rats.