Reactive Oxygen Species in the Presence of High Glucose Alter Ureteric Bud Morphogenesis

Abstract

Renal malformations are a major cause of childhood renal failure. During the development of the kidney, ureteric bud (UB) branching morphogenesis is critical for normal nephrogenesis. These studies investigated whether renal UB branching morphogenesis is altered by a high ambient glucose environment and studied underlying mechanism(s). Kidney explants that were isolated from different periods of gestation (embryonic days 12 to 18) from Hoxb7-green fluorescence protein mice were cultured for 24 h in either normal D-glucose (5 mM) or high D-glucose (25 mM) medium with or without various inhibitors. Alterations in renal morphogenesis were assessed by fluorescence microscopy. Paired-homeobox 2 (Pax-2) gene expression was determined by real-time quantitative PCR, Western blotting, and immunohistology. The results revealed that high D-glucose (25 mM) specifically stimulates UB branching morphogenesis via Pax-2 gene expression, whereas other glucose analogs, such as D-mannitol, L-glucose, and 2-deoxy-Dglucose, had no effect. The stimulatory effect of high glucose on UB branching was blocked in the presence of catalase and inhibitors of NADPH oxidase, mitochondrial electron transport chain complex I, and Akt signaling. Moreover, in in vivo studies, it seems that high glucose induces, via Pax-2 (mainly localized in UB), acceleration of UB branching but not nephron formation. Taken together, these data demonstrate that high glucose alters UB branching morphogenesis. This occurs, at least in part, via reactive oxygen species generation, activation of Akt signaling, and upregulation of Pax-2 gene expression.

Post-weaning high-fat diet accelerates kidney injury, but not hypertension programmed by maternal diabetes

“…Renal injury has been reported previously in our Dia-ND mice (9)(10)(11)(12)(13). In this work, we found that HFD augmented TGFβ1 and collagen IV gene expression, increased renal lipid accumulation, as well as heightened oxidative stress in both glomerular and tubular compartments in the kidneys of Dia-HF mice, resulting in significant glomerulosclerosis, tubular fibrosis, and apoptosis.…”

“…Such offspring showed impaired nephrogenesis resulting in nascent nephron deficiency in neonate and manifested hypertension, glucose intolerance, and kidney injury in adulthood. The possible mechanisms involved in those phenomena include reactive oxygen species (ROS) elevation and activation of the nuclear factor-kappa B (NFkB), TGFβ1, and p53 pathways (9)(10)(11)(12)(13).…”

Association of PAX2 with Cell Apoptosis in Unilateral Ureteral Obstruction Rats

“…The results from those four studies mentioned above might draw a conclusion that the increased expression of PAX2 took part in the progression of RIF. Furthermore, ROS could induce the PAX2 expression, 49,50 and overexpression of PAX2 was found in the renal tissue affected by RIF. 30 PAX2 was associated with the development of RIF.…”

Redox Control of Renal Function and Hypertension

“…Autosomal recessive mutations in the coenzyme Q(10) protein leads to glomerular damage via decreased activity of complex II ϩ III in abnormal mitochondrions in podocytes (54). Blockade of mitochondrial complex I leads to lack of ureteric bud-branching morphogenesis in response to high glucose (383). Hyperglycemia induces mitochondrial electron-transport chain enzymes in cultured human mesangial cells to increase ROS production, leading to NF-B activation and COX-2 protein expression (162).…”