Diabetic nephropathy (DN) is a major complication of diabetes. It afflicts 30 to 50% of type I diabetics and 20% of type 2 diabetics. It is one of the principal cuases of chronic renal insufficiency in Europe and in the United States. Moreover, the presence of a microalbuminuria, which is an early marker of DN, triples the incidence of cardiovascular accidents. Thus DN constitutes a major medical and public health problem. However, its molecular and cellular mechanisms remain largely unknown.

Family studies have suggested that genetic factors may modulate the risk of nephropathy. A susceptibility gene for this disease, the gene for the angiotensin-converting enzyme (ACE), has been identified. Polymorphisms of this gene (and in particular an insertion/deletion at the level of intron 16) are in fact associated with enzyme levels and the risk of the appearance of DN as well as the rate of its progression. In the mouse, a titration protocol for the ACE gene has confirmed the human data and enabled the establishment of causality between the level of constitutive synthesis of ECA and the progression of albuminuria. These mice constitute a monogenic model of graded severity of DN which is especially useful for the study of the molecular and cellular mechanisms implicated in the disease.
Sequencing data is an essential prerequisite for the continuation of the studies which have already been carried out on diabetic nephropathy. The identification of early altered transcripts in DN which are implicated in the deleterious effects of the angiotensin I converting enzyme on the diabetic kidney should make it possible to generate hypotheses which can then be tested specifically:

• targeted studies by in situ hybridization and RT-PCR, studies of proteins and cell signal transduction pathways.
• studies in humans of candidate genes identified within the framework of population and cohort studies concerning the development of vascular and renal complications of diabetes

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