Objective Renal fibrosis plays a pivotal role in the progression of renal dysfunction in diabetic kidney disease (DKD), with the macrophage-to-myofibroblast transition (MMT) serving as a central mechanism driving the advancement of renal fibrosis to end-stage renal disease (ESRD) in various chronic kidney conditions. Although the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin (DAPA) slows renal function decline in DKD, its antifibrotic mechanisms remain unclear. This study aimed to elucidate whether DAPA ameliorates renal fibrosis by suppressing MMT, and the underlying molecular mechanisms. Methods We established a DKD model in male C57BL/6J mice by inducing them with a high-fat diet (HFD) followed by streptozotocin (STZ) injection. The effects of DAPA on renal function parameters (serum creatinine (Scr), urinary albumin-to-creatinine ratio (UACR)), and renal pathological injury, fibrosis markers (α-smooth muscle actin (α-SMA), type I collagen (Col-I)) were comprehensively evaluated. Immunofluorescence (IF) and Western blot were employed to analyze MMT progression (F4/80 + /α-SMA + double-positive cells) and TGF-β1-Smad3/7 pathway activity. Results DAPA significantly reduced blood glucose levels, mitigated weight loss, and effectively inhibited type 2 diabetes-induced increase in Scr (43.78 ± 3.84 vs. 33.93 ± 6.77 µmol/L, P < 0.05) and UACR (89.17 ± 16.33 vs. 52.51 ± 10.51 mg/g, P < 0.05) in DKD mice. DAPA significantly attenuated glomerular hypertrophy, mesangial hyperplasia, and vacuolar degeneration of the tubular epithelium in DKD mice, while concurrently reducing glomerular and tubular injury scores, as well as the renal interstitial fibrosis area ( P < 0.05). IF revealed increased MMT within the renal tubulointerstitium in DKD mice, accompanied by elevated deposition of α-SMA and Col-I. DAPA treatment markedly reduced F4/80 + macrophage infiltration and F4/80 + /α-SMA + and F4/80 + /Col-I + double-positive MMT cells, with decreased α-SMA and Col-I expression ( P < 0.05). Additionally, TGF-β1 and phosphorylated Smad3 (p-Smad3) expression were significantly upregulated in DKD mice, whereas Smad7 was downregulated ( P < 0.05). DAPA treatment significantly reduced TGF-β1 and p-Smad3 levels and restored Smad7 expression, rebalancing the Smad3/Smad7 axis ( P < 0.05). Therefore, we propose that DAPA likely alleviates renal fibrosis in DKD by modulating renal TGF-β1 activity and restoring the Smad3/Smad7 balance, thereby suppressing MMT. Conclusion This study is the first to reveal that DAPA is highly likely to exert anti-fibrotic effects through a novel mechanism involving targeted modulation of the TGF-β1-Smad3/7 axis to inhibit MMT, thereby laying a theoretical foundation and identifying a potential therapeutic target for precision treatment of DKD.
X et al. (Wed,) studied this question.
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