TABLE 1.

Summary of Novel Therapies

AGEs Therapies
Therapeutic	Mechanism of Action	Model	Results	Reference
Alagebrium	Crosslink breaker	STZ-induced diabetic mouse	Reduced renal AGE accumulation, glomerular expansion, expression of MCP-1 and ICAM-1	Watson et al., 2012 (27)
Alagebrium	Crosslink breaker	db/db mouse	Reduced oxidative stress in kidneys and activity of PKCα/β	Park et al., 2011 (63)
Pyridoxamine	AGE inhibitor	STZ-induced diabetic rat	Attenuated increase in albuminuria and reduced levels of AGE and CML	Degenhardt et al., 2002 (30)
Pyridoxamine	AGE inhibitor	Type 2 diabetic KK-Ay/Ta mouse	Improved levels of ACR, reduced glomerular accumulation of CML and reduced renal expression of TGF-β1	Tanimoto et al., 2007 (29)
Pyridoxamine	AGE inhibitor	Human with T1DM or T2DM	Reduced change in serum creatinine and urinary TGF-β1 and AGEs	Williams et al., 2007 (31)

Nrf2 Agonists
Therapeutic	Mechanism of Action	Model	Results	Reference
Sulforaphane	Disruption of the Keap1-Nrf2 complex	STZ-induced diabetic mouse	Attenuated increase in ACR, reduced GBM thickening, mesangial cell proliferation, and renal tubular epithelial damage. Decreased expression of TGF-β1 and CTGF	Cui et al., 2012 (34)
Sulforaphane	Disruption of the Keap1-Nrf2 complex	STZ-induced diabetic mouse	Attenuated ACR, glomerulosclerosis, GBM thickening. Reduced renal oxidative stress, TGF-β1, and extracellular matrix deposition	Zheng et al., 2011 (64)
MG132	Induction of Nrf2 via protease inhibition	T1DM OVE26 mouse	Attenuated renal hypertrophy, BUN, and ACR. Reduced glomerular enlargement, expansion of mesangial matrix, and epithelial damage. Decreased renal expression of TGF-β1 and CTGF	Cui et al., 2013 (65)
tBHQ	Disruption of the Keap1-Nrf2 complex	STZ-induced diabetic mouse	Reduced renal hypertrophy, fibronectin accumulation, and glomerular malondialdehyde	Li et al., 2011 (41)
dh404	Disruption of the Keap1-Nrf2 complex	STZ-induced diabetic ApoE−/−mice	Attenuated ACR, mesangial expansion, glomerular injury, and improved renal tubular injury in diabetic mice. Reduced oxidative stress and proinflammatory mediators TNF-α, ICAM-1, VCAM-1, and MCP-1	Tan et al., 2014 (66)

PKC Inhibitors
Therapeutic	Mechanism of Action	Model	Results	Reference
LY333531 (Ruboxistaurin)	PKCβI/II inhibitor	Diabetic rat	Improved eGFR, albumin excretion rate, and retinal circulation in diabetic rats	Ishii et al., 1996 (45)
Ruboxistaurin	PKCβI/II inhibitor	(mRen-2)27 rat	Reduced albuminuria, glomerulosclerosis, tubulointerstitial pathology, and expression of TGF-β	Kelly et al., 2003 (47)
Ruboxistaurin	PKCβI/II inhibitor	Human with T2DM	Reduced increase in urinary TGF-β:creatinine ratio	Gilbert et al., 2007 (51)
Ruboxistaurin	PKCβI/II inhibitor	Human with T2DM	Decreased ACR and attenuated loss of eGFR	Tuttle et al., 2005 (50)
Ruboxistaurin	PKCβI/II inhibitor	Human with T2DM	Similar outcomes in patients who received placebo and patients who received ruboxistaurin	Tuttle et al., 2007 (67)

ACR, albumin-to-creatinine ratio; AGE, advanced glycation end product; ApoE−/−; apolipoprotein E deficient; BUN, blood urea nitrogen; CML, carboxylmethyllysine; GBM, glomerular basement membrane; ICAM-1, intercellular adhesion molecule 1; Keap1, Kelch-like ECH-associated protein; MCP-1, monocyte chemoattractant protein 1; (mRen-2)27, hypertensive Ren-2 transgenic; Nrf2, nuclear factor (erythroid-derived 2)-like 2; PKCα/β, protein kinase C alpha/beta; STZ, streptozotocin; T1DM, type 1 diabetes; T2DM, type 2 diabetes; TGF-β, transforming growth factor β (if a 1 appears, the specific isoform TGF-β1 was studied); TNF-α, tumor necrosis factor alpha; VCAM-1, vascular cell adhesion protein 1.