Table 1.
Effects of Sodium–glucose cotransporter 2 (SGLT2) inhibitors (including phlorizin) on diabetic nephropathy (DN) in experimental models. SGLT2 inhibitors have been shown to attenuate DN in both type 1 diabetes (T1D) and type 2 diabetes (T2D) animal models. High-dose but not lose-dose SGLT2 inhibitors ameliorate albuminuria, but renal inflammation, oxidative stress, and fibrotic gene expression are inhibited regardless of the dose.
| Study | Model | Drug/Dose/Duration | Major Effects |
|---|---|---|---|
| Malatiali et al. [29] | STZ-diabetic rats | phlorizin, 800 mg/kg, 6 days (initial dose: 400 mg/kg) | ↓ Glomerular hyperfiltration, |
| ↓ Kidney size, | |||
| ↓ Oxidative stress | |||
| Osorio et al. [30] | STZ-diabetic rats | phlorizin, 400 mg/kg, 30 days | ↓ Oxidative stress |
| Vallon et al. [27] | Akita mice | empagliflozin, 300 mg/kg, 15 weeks | ↓ Glomerular hyperfiltration, |
| ↓ Albuminuria, | |||
| ↓ Kidney Weight, | |||
| ↓ Inflammation | |||
| Gembardt et al. [31] | BTBR ob/ob mice | empagliflozin, diet containing 300 ppm of empagliflozin, 12 weeks | ↓ Albuminuria, |
| ↓ Glomerular hypertrophy, | |||
| ↓ Inflammation, | |||
| ↓ Mesangial matrix expansion | |||
| BTBR ob/ob mice with hypertension (angiotensin-II infusion) | empagliflozin, 300 ppm, 12 weeks | ↓ Albuminuria | |
| Ojima et al. [32] | STZ-diabetic rats | empagliflozin, 10 mg/kg, 4 weeks | ↔ Albuminuria, |
| ↓ AGE/RAGE, | |||
| ↓ Oxidative stress, | |||
| ↓ Inflammation, | |||
| ↓ Fibrotic gene markers, | |||
| ↓ Tubular injury | |||
| Gangadharan Komala et al. [38] | eNOS-deficient-STZ-diabetic mice | empagliflozin, 10 mg/kg, 19 weeks | ↔ Albuminuria, |
| ↔ Glomerulosclerosis, | |||
| ↔ Interstitial fibrosis, | |||
| ↔ TGF-β, | |||
| ↔ Fibronectin, | |||
| ↔ MCP-1 | |||
| Gallo et al. [39] | db/db mice | empagliflozin, 10 mg/kg, 10 weeks | ↔ Albuminuria |
| ↓ Profibrotic gene markers, | |||
| ↓ Fibronectin, | |||
| ↓ TGF-β | |||
| Kojima et al. [34] | T2DN rats (McWi strain) | luseogliflozin, 10 mg/kg, 3 weeks | ↔ Proteinuria |
| ↓ Glomerulosclerosis | |||
| Terami et al. [35] | db/db mice | dapagliflozin, 0.1 mg/kg or 1.0 mg/kg, 12 weeks | ↓ Albuminuria, |
| ↓ Oxidative stress, | |||
| ↓ Inflammation | |||
| Hatanaka et al. [36] | Akita mice | dapagliflozin, 1.0 mg/kg, 12 weeks | ↓ Albuminuria, |
| ↓ Oxidative stress, | |||
| ↓ Macrophage infiltration | |||
| Nagata et al. [37] | db/db mice | tofogliflozin, Diet containing 0.005% or 0.015% of tofogliflozin, 8 weeks | ↓ Albuminuria, |
| ↓ Glomerular hypertrophy | |||
| Wang et al. [23] | db/db mice | JNJ39933673, Diet containing 0.07 g/kg of JNJ39933673, 12 weeks | ↓ Albuminuria, |
| ↓ Mesangial expansion, | |||
| ↓ Podocyte injury, | |||
| ↓ Renal lipid accumulation |
STZ: Streptozotocin; eNOS: Endothelial nitric oxide synthase; TGF-β: Transformative growth factor β; MCP-1: Monocyte chemoattractant protein-1; AGE–RAGE: Advanced glycated end products-receptor for AGE; T2DN: Type 2 diabetic nephropathy.