ObjectiveThe purpose of this paper is to evaluate the possible prophylactic effects ofsaxagliptin (SAX), a dipeptidyl peptidase 4 inhibitor, andHibiscus sabdariffaLinn extract (HSE) and their combination againstNω-nitro-L-arginine methylester (L-NAME)-induced hypertensive nephropathy in rats; in addition, theireffects on proinflammatory and fibrogenic cytokines involved in renal injuryinduced by hypertension were investigated.Materials and methodsRats were randomly divided into five groups (eight each) as follows: control group;L-NAME-treatedgroup(50mg/kg/dayindrinkingwater);SAX+L-NAME-treatedgroup(10mg/kg/day postoperatively); HSE+L-NAME-treated group (100mg/kg/day postoperatively); SAX+HSE+L-NAME-treated group that received the same doses.Systolic blood pressure was measured. Kidney function tests (blood urea nitrogen,serum creatinine, total protein contents in 24-h urine, and creatinine clearance rate)andrenaltissueoxidativebiomarkers(malondialdehyde,glutathione,andglutathioneperoxidase activity) were assessed. Proinflammatory cytokines (tumor necrosisfactor-αand interleukin-6) levels were assessed in renal tissue homogenate; inaddition, renal tissue transforming growth factor-β1 mRNA expression level wasassayed. Histopathological analysis of the kidney and scoring were also performed.ResultsAdministration of either SAX or HSE for 8 weeks attenuatedL-NAME-inducedincreased oxidative stress, inflammation, and fibrosis in the kidney of rats,associated with improvement of the impaired renal function and histopathologicalchanges,buttheircombinationwasfoundtobemoreeffectiveintheprotectionagainstL-NAME-induced hypertensive renal damage than each drug alone.ConclusionA combination of SAX and HSE protected the kidney tissue againstL-NAME-induced hypertensive nephropathy through their antioxidant, anti-inflammatory,and antifibrotic activities.