Table 2.
Agents for nonspecific inhibition of CCN2 expression in diabetic nephropathy.
| Agents | Subjects | Treatment plan | Pathway | Outcome |
|---|---|---|---|---|
| Losartan [43] | T1 DN patients | 50, 100, and 150 mg/day for 2 months, then 100 mg for 36 months | Losartan persistently decreased urinary CCN2 excretion, which correlated with a slower rate of decline in GFR | |
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| Spironolactone [46] | MCs, PTCs T2DM rats |
100 nM for 24 h; 20 mg/kg/day, p.o. for 8 months |
TGF-beta1-independent pathway | Spironolactone suppressed the production of CCN2 in MCs, PTCs, and T2DM rat model. Spironolactone reduced urinary protein and albumin excretion. |
|
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| Fasudil [52] | T1DM rats | 10 mg/kg/day IG for 30 days |
Rho/Rho-kinase pathway | Fasudil inhibited CCN2 expression in the renal cortex of diabetic rats, with no affection of plasma glucose, blood pressure, and creatinine clearance in the diabetic rats. Fasudil suppressed urinary excretion of albumin. |
|
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| Fasudil [54] | HMCs | HG 30 mmol/L fasudil 25, 50, and 100 µmol/L for 12, 24, 36, 48, and 72 h |
Rho/Rho-kinase pathway | Fasudil reduced CCN2 mRNA expression and protein secretion. |
|
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| Fluorofenidone [65] (AKF-PD) | MMC | TGF-β1 (1 ng/mL) fluorofenidone (2 mM) for 24 hours |
ERK and p38 pathways | Fluorofenidone reduced TGF-β1-induced CCN2 expression. |
|
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| Fluorofenidone [66] (AKF-PD) | HK2 | TGF-β1 (5 ng/mL) AKF-PD 1 mM, 2 mM For 48 h |
Downregulation of p-Smad2 and p-Smad3 proteins. | AKF-PD downregulated TGF-β1-induced CCN2 expression and attenuated EMT. |
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| Exendin-4 [73] | HMC | HG 30 mmol/L Ex-4 0.03, 0.3, and 3 nmol/L for 24 hours |
cAMP/PKA pathway | Exendin-4 decreased HG-induced the expression of TGF-β1 and CCN2. |
|
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| PCB [78] PCE [78] |
HRMC db/db mice |
HG (33 mM) PCB 10, 20 μg/mL for 3 days 10 mg/kg PCE, p.o. daily for 8 weeks. |
IL-8-Tyk2-STAT signaling | PCB suppressed IL-8-instigated CCN2 expression and collagen IV deposition. PCE extenuated the expression of TGF-β, CCN2, and collagen IV in renal tissues, alleviated glomerulosclerosis and renal filtration dysfunction, and lessened heavy proteinuria. |
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| PCA [79] | HRMC | HG (33 mM) PCB 10, 20, and 25 μg/mL for 3 days |
TGF-β-SMAD signal NF-κB signaling MCP signaling |
PCA attenuated HG-induced CCN2 expression and collagen IV production. PCA reversed HG-reduced MT-1 MMP and HG-augmented TIMP-2 expression. PCA inhibited HG-induced ICAM-1 and MCP-1 expression. PCA attenuated renal fibrosis and mesangial inflammation. |
T1 DN: type 1 diabetes nephropathy; GFR: glomerular filtration rate; MCs: mesangial cells; PTCs: proximal tubular cells; T2DM: type 2 diabetes mellitus; IG: intragastric; HMCs: human mesangial cells; MMC: mouse mesangial cells; HK2: human renal proximal tubular epithelial cells; HRMC: human renal mesangial cells; PCB: purple corn butanol fraction; PCE: extracts of purple corn; PCA: purple corn anthocyanins; MCP-1: monocyte chemoattractant protein-1; ICAM-1: intracellular cell adhesion molecule-1.