Potential Renoprotective Agents through Inhibiting CTGF/CCN2 in Diabetic Nephropathy

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
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.
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.
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.
Fluorofenidone [65] (AKF-PD)	MMC	TGF-1 (1 ng/mL); fluorofenidone (2 mM) for 24 hours	ERK and p38 pathways	Fluorofenidone reduced TGF-1-induced CCN2 expression.
Fluorofenidone [66] (AKF-PD)	HK2	TGF-1 (5 ng/mL); AKF-PD 1 mM, 2 mM; For 48 h	Downregulation of p-Smad2 and p-Smad3 proteins.	AKF-PD downregulated TGF-1-induced CCN2 expression and attenuated EMT.
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-1 and CCN2.
PCB [78]; PCE [78]	HRMC; db/db mice	HG (33 mM); PCB 10, 20 g/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-, CCN2, and collagen IV in renal tissues, alleviated glomerulosclerosis and renal filtration dysfunction, and lessened heavy proteinuria.
PCA [79]	HRMC	HG (33 mM); PCB 10, 20, and 25 g/mL; for 3 days	TGF--SMAD signal; NF-B 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.