Although both
sodium glucose co-transporter 2 inhibition by
dapagliflozin and
thiazolidinedione,
pioglitazone have
glucose-lowering and anti-inflammatory effects, the therapeutic efficacy of their combination on
diabetic nephropathy has not been investigated. 9-week-old male db/db mice were randomly assigned to 4 groups and administrated with (1) vehicle, (2)
dapagliflozin, (3)
pioglitazone, or (4)
dapagliflozin and
pioglitazone combination. Human proximal tubule (HK-2) cells were treated with
glucose or
palmitate acid in the presence of medium,
dapagliflozin,
pioglitazone, or both. Glomerular tuft area and mesangial expansion of the kidney more reduced in the combination group compared to control and single
therapy groups. Podocyte foot process width and glomerular basement membrane thickness decreased regardless of treatment, while the combination group showed the slowest renal
hypertrophy progression (P < 0.05). The combination treatment decreased MCP-1, type I and IV
collagen expression in the renal cortex. Only the combination treatment decreased the expression of
angiotensinogen,
IL-6, and TGF-β while it enhanced HK-2 cell survival (all P < 0.05). In conclusion,
dapagliflozin and
pioglitazone preserved renal function, and combination
therapy showed the greatest benefit. These findings suggest that the combination
therapy of
dapagliflozin with
pioglitazone is more effective than the single
therapy for preventing the progression of nephropathy in patients with
type 2 diabetes.