Ibrahim Tawhari; Hanan H. Alshehri; Saif A. Alqahtani; Mohammed Tawhari; Alia Albawardi; Hind Zafrah; Rehab M. Badi; Muataz E. D. Mohammed; Asmaa M. ShamsEldeen; Amal F. Dawood; Norah M. Alzamil & Bahjat Al-Ani

Urinary tract infection (UTI) is common in patients with uncontrolled diabetes mellitus. However, the relationship between diabetic nephropathy associated with hypertension (DNH) and two key UTI markers–leukocyturia and urinary nitrite–has not previously been investigated in animal models, either in the presence or absence of antidiabetic drug treatment. In humans, establishing a direct association between diabetic nephropathy and hypertension is challenging, as ageing independently contributes to arterial stiffening and elevated blood pressure. To overcome this limitation, DNH was induced in age-matched, non-diabetic, and normotensive rats, allowing the effects of diabetes-related hypertension to be examined independently of ageing. Therefore, in addition to the control and untreated diabetic rats, two diabetic groups were treated with metformin (200 mg/kg) and metformin plus sitagliptin (200 mg/kg plus 100 mg/kg sitagliptin), and all animals were culled at week 12 for histopathological, morphological, immunohistochemical, biochemical, and physiological analyses. DNH was confirmed in the diabetic group, as demonstrated by increased kidney tissue levels of nitrosative stress and inflammatory cell infiltration, kidney mesangial expansion and tubular necrosis, renal fibrosis, albuminuria, and hypertension. Additionally, all untreated rats with DNH tested positive for leukocyturia and urinary nitrite in addition to exhibiting proteinuria and ketonuria. In contrast, all control rats showed negative results, and no haematuria was observed in either group. Furthermore, 92 % of rats treated with the antidiabetic drugs demonstrated negative glucosuria, which correlated with a substantial reduction in UTI biomarkers. Notably, metformin plus sitagliptin exhibited the most effective protection. Thus, we induced a rat model of DNH supported by pathological and morphological changes, and identified urinary nitrite and leukocyturia as potential additional biomarkers of DNH, while antidiabetic treatments confer protective effects beyond glycaemic control. Our data reflect patterns observed in uncontrolled diabetes in humans, and suggests that their detection may warrant early clinical investigation and intervention.

KEY WORDS: Diabetic nephropathy; Hypertension; Biomarkers; UTI; Antidiabetic drugs; Animal model.

TAWHARI, I.; ALSHEHRI, H. H.; ALQAHTANI, S. A.; TAWHARI, M.; ALBAWARDI, A.; ZAFRAH, H.; BADI, R. M.; MOHAMMED, M. E. D.; SHAMSELDEEN, A. M.; DAWOOD, A. F.; ALZAMIL, N. M. & AL-ANI, B. Animal model of diabetic nephropathy associated with hypertension: Identifying urinary tract infection biomarkers protected by antidiabetic drugs, similar to patients with uncontrolled diabetes. Int. J. Morphol., 44(3):1030-1038, 2026.