Retatrutide treatment in streptozotocin-induced diabetic rats: renal inflammatory cytokines, HIF‑1α expression, and histopathological injury profile.

This study investigated whether Retatrutide, a triple incretin agonist, attenuates early diabetes-associated renal injury in a streptozotocin-induced rat model, and whether any protective effect is mediated through modulation of inflammatory cytokines (IL-1β, TNF-α) and HIF-1α gene expression in kidney tissue. Male Sprague-Dawley rats were divided into four groups: control, STZ-induced diabetic, STZ plus Retatrutide, and Retatrutide alone. Diabetes was induced via a single intraperitoneal STZ injection; Retatrutide was administered subcutaneously for 21 days at a dose adapted from prior metabolic studies. Renal tissue underwent ELISA for interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α), quantitative real-time PCR for HIF-1α expression, and semi-quantitative histopathological scoring of cortical and medullary parameters including haemorrhage, tubular dilatation, inflammatory cell infiltration, tubular vacuolisation, interstitial fibrosis, and intraluminal debris. STZ-induced rats exhibited significantly elevated cortical and medullary histopathological scores and increased renal IL-1β levels relative to controls, confirming successful early injury induction. Retatrutide did not produce statistically significant histopathological protection, although STZ plus Retatrutide animals showed consistently lower damage scores than STZ-only animals, corresponding to large standardised effects (Cliff's δ = 0.90 in the cortex and 0.85 in the medulla) that could not be confirmed under family-wise error correction. HIF-1α expression was highest in the untreated diabetic group and was significantly lower in Retatrutide-treated diabetic animals (S vs. SR, p = 0.020), whereas Retatrutide alone did not alter expression relative to controls. TNF-α did not differ significantly in any pairwise comparison; levels in Retatrutide-treated diabetic animals were nonetheless comparable to controls (g* = 0.03). Retatrutide selectively modulated HIF-1α transcriptional levels in the acute STZ model without statistically confirmed histopathological renoprotection, and without evidence of intrinsic renal toxicity. Because the acute STZ model reflects insulin-deficient rather than T2DM-like disease, the model itself is a critical limitation; chronic type 2 diabetes models, together with longer treatment durations and refined dosing regimens, are required to determine whether the observed early molecular effects translate into structural renal benefit.