Null mutations at the p66 and bradykinin 2 receptor loci induce divergent phenotypes in the diabetic kidney.

Candidate genes have been identified that confer increased risk for diabetic glomerulosclerosis (DG). Mice heterozygous for the Akita (Ins2(+/C96Y)) diabetogenic mutation with a second mutation introduced at the bradykinin 2 receptor (B2R(-/-)) locus express a disease phenotype that approximates human DG. Src homology 2 domain transforming protein 1 (p66) controls mitochondrial metabolism and cellular responses to oxidative stress, aging, and apoptosis. We generated p66-null Akita mice to test whether inactivating mutations at the p66 locus will rescue kidneys of Akita mice from disease-causing mutations at the Ins2 and B2R loci. Here we show null mutations at the p66 and B2R loci interact with the Akita (Ins2(+/C96Y)) mutation, independently and in combination, inducing divergent phenotypes in the kidney. The B2R(-/-) mutation induces detrimental phenotypes, as judged by increased systemic and renal levels of oxidative stress, histology, and urine albumin excretion, whereas the p66-null mutation confers a powerful protection phenotype. To elucidate the mechanism(s) of the protection phenotype, we turned to our in vitro system. Experiments with cultured podocytes revealed previously unrecognized cross talk between p66 and the redox-sensitive transcription factor p53 that controls hyperglycemia-induced ROS metabolism, transcription of p53 target genes (angiotensinogen, angiotensin II type-1 receptor, and bax), angiotensin II generation, and apoptosis. RNA-interference targeting p66 inhibits all of the above. Finally, protein levels of p53 target genes were upregulated in kidneys of Akita mice but unchanged in p66-null Akita mice. Taken together, p66 is a potential molecular target for therapeutic intervention in DG.

A Case of Transient Gestational Hyperthyroidism Complicated With Acute Liver Injury Successfully Treated With Plasma Exchange.

Therapeutic Plasma Exchange (TPE) in pregnancy is rare due to the uncertainty of efficiency and safety in clinical practice. It is experience-based on extrapolation of efficacy and safety in non-pregnant populations than evidence-based. We reported a case of severe refractory hyperemesis gravidarum secondary to transient gestational hyperthyroidism in a first-trimester pregnancy, which was complicated by acute hepatic injury during the clinical course and successfully managed with TPE. Both the clinical picture and objective index were improved dramatically after plasma exchanges. Three sessions of plasma exchange provided a 61% decrease in serum FT4 (free thyroxine) concentration (4.34 ng/dL to 1.71 ng/dL) and 89% decrease in alanine aminotransferase (ALT) (647 units/L to 69 units/L). The patient's symptoms improved significantly after TPE. In two weeks follow-up visit, her thyroid function was in the recommended range of 1st-trimester pregnancy (1.06 ng/dL) and her liver function was normalized (ALT 15 units/L, aspartate aminotransferase {AST} 11 units/L). In conclusion, plasma exchange may be used as an alternative therapeutic option in pregnancy to manage transient hyperthyroidism who failed or was unable to tolerate or have contradictions to antithyroid medications and thyroidectomy. Our case provides evidence of TPE in the treatment of thyrotoxicosis in pregnancy.