Implications of Treatment That Target Protective Mechanisms Against Diabetic Nephropathy

Abstract

Summary Diabetes results in vascular changes and dysfunction, and vascular complications are the leading cause of morbidity and mortality in diabetic patients. There has been a continual increase in the number of diabetic nephropathy patients and epidemic increases in the number of patients progressing to end-stage renal diseases. To identify targets for therapeutic intervention, most studies have focused on understanding how abnormal levels of glucose metabolites cause diabetic nephropathy, which is of paramount importance in devising strategies to combat the development and progression of diabetic nephropathy. However, less studied than the systemic toxic mechanisms, hyperglycemia and dyslipidemia might inhibit the endogenous vascular protective factors such as insulin, vascular endothelial growth factor, and platelet-derived growth factor. In this review, we highlight the importance of enhancing endogenous protective factors to prevent or delay diabetic nephropathy.

Diabetes-Induced Reactive Oxygen Species: Mechanism of Their Generation and Role in Renal Injury

“…These deleterious effects may include but are not limited to proteinuria, hypertension, and thrombotic microangiopathy [248, 249]. For instance, cancer patients treated with bevacizumab, a humanized monoclonal antibody against VEGF, experienced aggravated pathological events including proteinuria, hypertension, extensive foot process effacement, and thrombotic microangiopathy [250]. Administration of anti-VEGF agent, mutation, or gene deletion of podocyte-specific VEGF in murine models also exhibited similar adverse consequences.…”

“…Administration of anti-VEGF agent, mutation, or gene deletion of podocyte-specific VEGF in murine models also exhibited similar adverse consequences. In addition, some studies have shown a beneficial role of VEGF which includes the prevention of progressive capillary rarefaction, promotion of capillary repair, improvement of renal injury, and prevention of functional and histologic abnormalities in diabetic nephropathy [250, 251]. In support of this evidence, Oltean et al's [251] transgenic podocyte-specific overexpression of VEGF-A165b in streptozotocin-induced diabetic mice demonstrated less glomerular hypertrophy, less mesangial expansion, and less GBM thickening.…”

Can Existing Drugs Approved for Other Indications Retard Renal Function Decline in Patients With Type 1 Diabetes and Nephropathy?

“…One approach is to identify novel drug targets by gaining a better understanding of the pathogenesis of diabetic nephropathy at the molecular level, as discussed by other articles in this issue 5–7 . However, going from the identification of a drug target to the development of a clinically effective intervention is a long and costly process and only a small number of compounds that enter the development pipeline end up being approved for clinical use.…”

Role of angiostatins in diabetic complications

“…По аналогии с опухолевым ростом, можно предположить, что в условиях дефицита супрессоров ангиогенеза (на ранних этапах ДН) в качестве антиангиогенной терапии была бы эффективна стратегия, направленная на ингибирование ростовых факторов, включая VEGF, и/или их рецепторов (FLK-1, FLT-1 и Tie2) [111,112]. Действительно, использование нейтрализующих VEGF специфических антител эффективно снижало степень гиперфильтрации, альбуминурии и гломерулярной гипертрофии почек у грызунов с экспериментальным диабетом [113].…”