Proteinuria in Type 2 Diabetic Patients with Renal Impairment:The Changing Face of Diabetic Nephropathy

Type 2 diabetic nephropathy (type 2 DN) patients traditionally develop significant proteinuria prior to the development of renal impairment. However, this clinical paradigm, based on observations prior to the widespread usage of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), has recently been questioned. 2,303 patients enrolled in the Sulodexide Overt Nephropathy Study (OVERT) were analyzed. Prior therapy with ACEi and/or ARB at the time of screening was recorded in 951 patients. 22% of patients had significant renal impairment with a PCR at screening o

Activation of the cyclin D1 gene by the E1A-associated protein p300 through AP-1 inhibits cellular apoptosis

The adenovirus E1A protein interferes with regulators of apoptosis and growth by physically interacting with cell cycle regulatory proteins including the retinoblastoma tumor suppressor protein and the coactivator proteins p300/CBP (where CBP is the CREB-binding protein). The p300/CBP proteins occupy a pivotal role in regulating mitogenic signaling and apoptosis. The mechanisms by which cell cycle control genes are directly regulated by p300 remain to be determined. The cyclin D1 gene, which is overexpressed in many different tumor types, encodes a regulatory subunit of a holoenzyme that phosphorylates and inactivates PRB. In the present study E1A12S inhibited the cyclin D1 promoter via the amino-terminal p300/CBP binding domain in human choriocarcinoma JEG-3 cells. p300 induced cyclin D1 protein abundance, and p300, but not CBP, induced the cyclin D1 promoter. cyclin D1 or p300 overexpression inhibited apoptosis in JEG-3 cells. The CH3 region of p300, which was required for induction of cyclin D1, was also required for the inhibition of apoptosis. p300 activated the cyclin D1 promoter through an activator protein-1 (AP-1) site at -954 and was identified within a DNA-bound complex with c-Jun at the AP-1 site. Apoptosis rates of embryonic fibroblasts derived from mice homozygously deleted of the cyclin D1 gene (cyclin D1−/−) were increased compared with wild type control on several distinct matrices. p300 inhibited apoptosis in cyclin D1+/+ fibroblasts but increased apoptosis in cyclin D1 −/− cells. The anti-apoptotic function of cyclin D1, demonstrated by sub-G1 analysis and annexin V staining, may contribute to its cellular transforming and cooperative oncogenic properties

Sulodexide for Kidney Protection in Type 2 Diabetes Patients With Microalbuminuria:A Randomized Controlled Trial

Background: Sulodexide, a heterogenous group of sulfated glycosaminoglycans, includes low-molecular-weight heparin (similar to 80% +/- 8%), high-molecular-weight heparin (similar to 5% +/- 3%), and dermatan (similar to 20% +/- 8%), with a mean molecular weight of similar to 9 kDa. The drug is absorbed orally and has no anticoagulant effect in the doses used. Small preliminary studies consistently showed sulodexide to be associated with decreased albuminuria in patients with diabetes. Study Design: We conducted a multicenter placebo-controlled double-blinded study to determine the effect of sulodexide on urine albumin excretion in patients with type 2 diabetic nephropathy. Setting & Participants: Patients with type 2 diabetes and urine albumin-creatinine ratios (ACRs) of 35-200 mg/g in men and 45-200 mg/g in women were enrolled. Serum creatinine level was Intervention: The study drug was sulodexide, 200 mg/d. Outcome & Measurements: The primary end point was normoalbuminuria (ACR 25%) or 50% decrease in baseline ACR. Results: In 1,056 randomly assigned patients with a mean baseline ACR of 107.8 +/- 83.7 mg/g, comparing the sulodexide versus placebo groups, the primary end point was achieved in 16.5% versus 18.4%; normoalbuminuria, in 7.9% versus 6.1%; and a 50% decrease in albuminuria, in 15.4% versus 17.6%. The relative probability of any given change in albuminuria was identical in both groups. Limitations: We were unable to determine whether the administered sulodexide was absorbed from the gastrointestinal tract. Conclusion: Sulodexide failed to decrease urine albumin excretion in patients with type 2 diabetic nephropathy and microalbuminuria. Am J Kidney Dis. 58(5):729-736. (C) 2011 by the National Kidney Foundation, Inc