The SGLT2i “canagliflozin” and the DPP-4i “sitagliptin” mitigate hypertensive nephropathy in adult male rats by modulating the Ang II/RAGE/Nox4/NLRP3 cascade

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Background: Hypertensive nephropathy (HN) with progressive renal damage is a common consequence of arterial hypertension (HTN). This study addresses the renoprotective attributes of the sodium-glucose cotransporter-2 inhibitor canagliflozin (Cana) and the dipeptidyl peptidase-4 inhibitor sitagliptin (Sita) on HN. Methods: Twenty-four adult male Wistar rats were categorized into four groups (six per group): control (CTRL), hypertensive nephropathy (HN); rats were given L-NAME (50 mg/kg, i.p., once a day), HN + Cana; rats were given L-NAME injections alongside oral Cana 10 mg/kg, and HN + Sita; rats were provided Sita 10 mg/kg concurrently with L-NAME injection. All regimens were given once a day for five consecutive weeks. Various physiological, biochemical, molecular, and histological parameters were evaluated. Results: Administration of Cana and Sita alleviated HN, as demonstrated by the notable improvements in renal functions, plasma angiotensin II, and systolic blood pressure. Additionally, a noticeable improvement in renal superoxide dismutase, malondialdehyde, NOD-like receptor family pyrin domain containing 3 inflammasome, interleukin (IL)-1β/-10, caspase 1, advanced glycation end products (AGEs), and relative expression of receptors for AGEs and nicotinamide adenine dinucleotide phosphate oxidase 4 was detected. Substantial enhancement in the microscopic structure of renal tissues, attenuated renal fibrosis, and decreased immunoreactivity of BAX and tumor necrosis factor-α highlighted these protective attributes. Conclusion: Both Sita and Cana successfully attenuated HTN and subsequent HN, thereby restoring renal function; however, Sita's protective profile was more favorable. These results implied that Sita and Cana might provide renoprotective impacts for kidney damage triggered by HTN in rats. However, additional research to investigate their possible modes of action is necessary.

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