Boldine Prevents Renal Alterations in Diabetic Rats

Abstract

Diabetic nephropathy alters both structure and function of the kidney. These alterations are associated with increased levels of reactive oxygen species, matrix proteins, and proinflammatory molecules. Inflammation decreases gap junctional communication and increases hemichannel activity leading to increased membrane permeability and altering tissue homeostasis. Since current treatments for diabetic nephropathy do not prevent renal damage, we postulated an alternative treatment with boldine, an alkaloid obtained from boldo with antioxidant, anti-inflammatory, and hypoglycemic effects. Streptozotocin-induced diabetic and control rats were treated or not treated with boldine (50 mg/Kg/day) for ten weeks. In addition, mesangial cells were cultured under control conditions or in high glucose concentration plus proinflammatory cytokines, with or without boldine (100 µmol/L). Boldine treatment in diabetic animals prevented the increase in glycemia, blood pressure, renal thiobarbituric acid reactive substances and the urinary protein/creatinine ratio. Boldine also reduced alterations in matrix proteins and markers of renal damage. In mesangial cells, boldine prevented the increase in oxidative stress, the decrease in gap junctional communication, and the increase in cell permeability due to connexin hemichannel activity induced by high glucose and proinflammatory cytokines but did not block gap junction channels. Thus boldine prevented both renal and cellular alterations and could be useful for preventing tissue damage in diabetic subjects.

Inhibition of glial hemichannels by boldine treatment reduces neuronal suffering in a murine model of Alzheimer's disease

“…This molecule is known for its cytoprotective effects mostly mediated by its potent antioxidant properties reported in diverse i n vitro preparations as well as in animal models of diabetes, hypertension and atherosclerosis (Lau, Ling, Murugan, & Mustafa, ; O'Brien, Carrasco‐Pozo, & Speisky, ; Santanam Penumetcha, Speisky, & Parthasarathy, ). However, it was recently reported to block HCs and not gap junctions in mesangial cells in culture by a mechanism yet unknown but independent of its antioxidant property (Hernández‐Salinas et al, ). Interestingly, this molecule can be administered in vivo via the drinking water without secondary toxic effects and reaches the brain (de Lima et al, ; Loghin et al, ) although this issue might not be critical since in most brain diseases and injuries its passage to the brain parenchyma should be facilitated since the blood brain barrier (BBB) is weakened (Zlokovic, ).…”

Mind the gap: connexins and cell–cell communication in the diabetic kidney

“…The study demonstrated that under resting conditions, mesangial hemi-channels had a low open-state probability. However, glucose, IL-1β and TNF-α all increased hemichannel activity, even at negative membrane potential and in the presence of extracellular divalent cations [57].…”

“…A recent study examined a role for boldine, an alkaloid with antioxidant, antiinflammatory, and hypoglycaemic effects in the reversal of renal complications in the STZ-induced diabetic rat [57]. The study demonstrated that under resting conditions, mesangial hemi-channels had a low open-state probability.…”

Cell-cell communication in diabetic retinopathy

“…Boldine, an alkaloid antioxidant with anti-inflammatory and hypoglycemic effects, has been shown to prevent HG-induced downregulation of gap junctional communication by improving gap junction-mediated cell coupling as well as increasing the relative level of Cx43 in mesangial cells (Hernandez-Salinas, Vielma, Arismendi, Boric, Saez & Velarde, 2013). In addition, boldine reduced membrane permeability in mesangial cells grown in HG condition with pro-inflammatory cytokines, associated with diabetic nephropathy (Hernandez-Salinas et al, 2013). Studies have shown that insulin treatment in diabetic rats can also prevent downregulation of intercellular communication in retinal pericytes, as determined by increased coupling of neurobiotin, a gap junction-permeant tracer (Oku et al, 2001).…”