Inhibition of advanced glycation end products: an implicit goal in clinical medicine for the treatment of diabetic nephropathy?
Several factors have been incriminated in the genesis of diabetic nephropathy. To elucidate their interplay, we have used a hypertensive, obese, diabetic rat model with nephropathy (SHR/NDmcr-cp) that mimics human type 2 diabetes. This model is characterized by hypertension, obesity with the metabolic syndrome, diabetes with insulin resistance, and intrarenal advanced glycation end product (AGE) accumulation. In order to achieve renoprotection, which was evaluated by histology and albuminuria, various therapeutic approaches were used: caloric restriction, antihypertensive agents (angiotensin II receptor blocker [ARB] and calcium channel blocker), lipid- (bezafibrate) or glucose-lowering (insulin and pioglitazone) agents, and cobalt chloride (a hypoxia-inducible factor activator). Altogether, renoprotection is not necessarily associated with blood pressure or glycemic control. By contrast, it is almost always associated with decreased AGE formation, with the exception of insulin, which induces hyperinsulinemia, eventually leading to an overproduction of transforming growth factor-beta. AGE formation is reduced directly by in vitro active compounds (e.g., ARBs) or indirectly by in vitro inactive compounds (e.g., pioglitazone and cobalt). In the latter cases, AGE reduction may reflect a decreased oxidative stress as it is concomitant with a marked reduction of oxidative stress markers. It remains to be seen whether the renoprotection offered by these various approaches may be additive.
Miyata
Toshio
T
Institute of Medical Sciences and Division of Nephrology, Hypertension and Metabolism, Tokai University School of Medicine, Kanagawa, Japan. t-miyata@is.icc.u-tokai.ac.jp
Izuhara
Yuko
Y
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001629:Bezafibrate / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000628:therapy; D004038:Diet, Reducing; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D017382:Reactive Oxygen Species; D001629:Bezafibrate