These findings suggest that candesartan, an ARB, reduces AGE accumulation and subsequent albuminuria by down-regulating the NADPH oxidase p47phox component and iNOS expression and by attenuating RAGE expression in type 2 diabetic KK/Ta mouse kidneys.

Genetic susceptibility plays an important role in the pathogenesis of diabetic nephropathy and type II diabetes. To identify the genetic polymorphisms associated with diabetic nephropathy and type II diabetes, we performed a genome-wide association study using single-nucleotide polymorphisms as genetic markers. We also analyzed polymorphisms within the genes encoding for the renin-angiotensin system that were considered as candidate genes for diabetic nephropathy susceptibility and the transcription factor 7-like 2 (TCF7L2) as a candidate for type II diabetes, in a large cohort of a Japanese population. A genome-wide association study identified SLC12A3 and engulfment and cell motility 1 gene as the new candidates for diabetic nephropathy and transcription factor-activating protein 2beta as a novel susceptibility gene for type II diabetes; this observation was based on the significant association between the polymorphisms within the genes and the corresponding diseases (P<0.0001). Further, we discovered that the genes encoding the angiotensin-converting enzyme, angiotensinogen, and angiotensin II type I receptor have a significant combinational effect on conferring susceptibility to diabetic nephropathy. Furthermore, TCF7L2 that has been reported as a convincing susceptibility gene for type II diabetes in Caucasian populations was also shown to be associated with type II diabetes in a Japanese population. These genes could be considered as strong susceptibility genes for diabetic nephropathy and type II diabetes in the Japanese, although the new candidates that have been identified by genome-wide screening need to be examined in greater detail by several replication studies.

The KK/Ta mouse strain serves as a suitable polygenic model for human type 2 diabetes. Using 93 microsatellite markers in 208 KK/Ta ؋ (BALB/c ؋ KK/Ta)F1 male backcross mice, we carried out a genome-wide linkage analysis of KK/Ta alleles contributing to type 2 diabetes and related phenotypes, such as obesity and dyslipidemia. We identified three major chromosomal intervals significantly contributing to impaired glucose metabolism: one quantitative trait locus for impaired glucose tolerance on chromosome 6 and two loci for fasting blood glucose levels on chromosomes 12 and 15. The latter two loci appeared to act in a complementary fashion. Two intervals showed significant linkages for serum triglyceride levels, one on chromosome 4 and the other on chromosome 8. The KK allele on chromosome 8 acts to promote serum triglyceride levels, whereas the KK allele on chromosome 4 acts to suppress this effect in a recessive fashion. In addition, it is suggested that the chromosome 4 locus also acts to downregulate body weight and that the chromosome 8 locus acts to upregulate serum insulin levels. Our data clearly showed that each disease phenotype of type 2 diabetes and related disorders in KK/Ta mice is under the control of separate genetic mechanisms. However, there appear to be common genes contributing to different disease phenotypes. There are potentially important candidate genes that may be relevant to the disease.

Although there were no significant correlations between urinary albumin levels and other diabetic phenotypes, the group of progeny homozygous for both UA-1 and alleles for fasting hyperglycaemia showed the highest urinary albumin levels. Thus, UA-1 appears to increase the risk of diabetic nephropathy, particularly in individuals susceptible to fasting hyperglycaemia, in a gene dosage-dependent manner. There are potentially important candidate genes that may be relevant to diabetic nephropathy.

The relationship between the levels of serum cystatin C and the prognostic stages of IgA nephropathy was determined in a multicenter trial in Japan. The levels of serum cystatin C in patients with IgA nephropathy were measured using the Dade Behring N Latex Cystain C assay. In 1995, the Joint Committee of the Special Study Group on Progressive Glomerular Diseases, Ministry of Health and Welfare of Japan, and the Japanese Society of Nephropathy reported four prognostic stages. These are: good prognosis group (Group I), relatively good prognosis group (Group II), relatively poor prognosis group (Group III), and poor prognosis group (Group IV), for this disease. Three‐hundred and six patients with IgA nephropathy and other glomerular diseases were examined. There were no significant changes in the levels of serum creatinine (Cr) or creatinine clearance (CCr) between Group I and Group II. The mean levels of serum cystatin C in Group II were significantly higher than those in Group I (P < 0.05). The mean levels of serum cystatin C in Group III or IV were significantly higher than those in Group I (P < 0.001, P < 0.005, respectively). These suggest that the measurement of serum cystatin C may predict the prognostic stages of patients with IgA nephropathy prior to renal biopsy. J. Clin. Lab. Anal. 15:25–29, 2001. © 2001 Wiley‐Liss, Inc.