Relevance of Aldo-keto Reductase Family Members to the Pathobiology of Diabetic Nephropathy and Renal Development

Aldo-keto reductases (AKRs) are a family of monomeric oxido-reductases with molecular weight ranging from 35-40 kDa and currently includes upwards of 60 members. They are expressed in a wide variety of tissues, where they catalyze the NADPH-dependent reduction of various aliphatic and aromatic aldehydes and ketones. The functions of most of the family members are not well defined. But two members, aldehyde reductase (AKRIA) and aldose reductase (AKRIB), have been extensively studied. The latter has received the most attention since being relevant to the complications of diabetes mellitus. It is up-regulated during hyperglycemia, and at the same time there is an increased activity of the sorbitol pathway and non-enzymatic glycation of proteins with ensuing damage in various tissues. It is developmentally regulated in the ocular lens, and is believed to modulate lens fiber morphogenesis during fetal life. Unlike the other AKR family members that are ubiquitously expressed, recently a renal-specific oxio-reductase has been described that is expressed exclusively in the proximal tubules. Although, it has no homology with other AKR members, it binds to NADPH with high affinity and is up-regulated in streptozotocin-induced diabetes in mice. It is also developmentally regulated and seems to selectively modulate renal tubulogenesis during embryonic life.