Background: An antidiabetic potential has long been reported for Rhus coriaria L. (sumac) and recent studies have proven a curative leverage against GM-induced nephrotoxicity. Aim of the work: The current study hypothesized a possible LRP2 expression modulatory ef-fect, as an ameliorative mechanism, produced by sumac in GM-induced nephrotoxicity in diabet-ic rats. Material and methods: Forty-two male albino rats were subdivided into control, sumac alone (orally for 14 days), DM (STZ, streptozotocin, single, intravenous), GM (intraperitoneal, once daily for 7 days), DM/GM, and DM/GM+sumac groups. Twenty-Four hrs after the last treat-ment, blood sampling was done for laboratory analysis of blood glucose, urea, and creatinine. The kidneys were harvested and subjected to RT-PCR quantification of LRP2 (megalin) mRNA levels, Hematoxylin and Eosin, Masson trichrome staining, and immunohistochemical assaying for P53, TNF-α, and megalin. Results: Diabetic rats showed altered biochemical and histological changes which increased in the GM alone group and showed more serious tubular and glomerular injury in GM/DM group associated with significant elevation of the renal functions, upregulation of megalin gene/protein expression, in addition to increased P53 and TNF-α immunoexpression. Sumac treatment down-regulated megalin gene/protein expression, coupled with regulation of P53 and TNF- α expres-sion and maintenance of the renal functions. Conclusion: GM injection in already existing STZ-induced diabetic rats led to more serious re-nal damage, and sumac co-treatment protected against this renal damage, might be via LRP2 blockage-dependent P53/TNF-α downregulation.