Decreased expression of vascular endothelial growth factor (VEGF) in the renal tubules is thought to cause progressive loss of the renal microvasculature with age. Mitochondrial dysfunction may be a principal phenomenon underlying the process of aging. The relation between VEGF expression and mitochondrial dysfunction in aging is not fully understood. We hypothesized that mitochondrial dysfunction blocks VEGF expression and contributes to impaired angiogenesis in the aging kidney. The aim of this study was to assess the role of mitochondria in VEGF expression in the aging rat kidney. We evaluated the accumulation of 8-hydroxy-2 0 -deoxyguanosine in mitochondrial DNA, as well as mitochondrial dysfunction, as assessed by electron microscopy of mitochondrial structure and histochemical staining for respiratory chain complex IV, in aging rat kidney. An increase in hypoxic area and a decrease in peritubular capillaries were detected in the cortex of aging rat kidneys; however, upregulation of VEGF expression was not observed. The expression of VEGF in proximal tubular epithelial cells in response to hypoxia was suppressed by the mitochondrial electron transfer inhibitor myxothiazol. Mitochondrial DNA-deficient cells also failed to upregulate VEGF expression under hypoxic conditions. These results indicate that impairment of VEGF upregulation, possibly as a result of mitochondrial dysfunction, contributes to impaired angiogenesis, which in turn leads to renal injury in the aging rat kidney.

Pancreatic endocrine cells synthesize and secrete pancreatic hormones such as insulin, glucagon, somatostatin and pancreatic polypeptide. These cells resemble neuronal cells in many respects. For example, they have excitable membranes and express voltagedependent sodium channels, voltage-dependent calcium channels and ionotropic glutamate receptor channels [1,2]; they express many proteins typical of neurons including synaptophysin, neurofilaments, tyrosine hydroxylase and g-amino butyric acid transporter [3,4]; and, they extend neurites when cultured under appropriate conditions [5]. Nevertheless, they arise from epithelial cells originating from the endoderm [3,5]. Hence, pancreatic endoderm-derived progenitor cells differentiate into endocrine cells, which express many neuronal marker proteins.Pancreatic AR42J cells are derived from a chemically induced pancreatic tumour and express both exocrine and neuroendocrine properties. These cells Diabetologia (1999)

Hyperfiltration in glomeruli is the most common pathway to progressive renal dysfunction. Moreover, reduction of renal mass by unilateral nephrectomy results in an immediate increase in glomerular flow to the remnant kidney, followed by compensatory glomerular hypertrophy. Reactive oxygen species (ROS) are involved in renal hypertrophic responses; however, the role of ROS in compensatory glomerular hypertrophy remains unclear. Therefore, this role was investigated in the present study. Wistar rats were randomly placed into two groups: uninephrectomized rats (Nx) and uninephrectomized rats treated with tempol (Nx + TP). The glomerular volume increased in the Nx 1 week after surgery, but was significantly suppressed in the Nx + TP. Levels of phospho-Akt and phospho-ribosomal protein S6, which are critical for cell growth and hypertrophy, were markedly increased in the glomeruli of the Nx, while tempol treatment almost abolished the activation of these proteins. These results suggest that ROS have important roles in compensatory hypertrophy in glomeruli.

The development of interstitial fibrosis occurs with aging. Impaired angiogenesis, associated with progressive loss of the renal microvasculature, is thought to be a cause of age-related nephropathy. However, the mechanism of capillary loss in aging kidney has not been fully elucidated. Angiostatin is a kringle-containing fragment of plasminogen and is a potent inhibitor of angiogenesis in vivo. Whether angiostatin generation is increased in the aging kidney has not been investigated. We examined 4, 10, 16, and 24-month-old Sprague-Dawley rats for angiostatin production and found that angiostatin generation was increased in aged rats. The protein expression and the activity of cathepsin D-the enzyme for angiostatin production-were increased in aged rats. In the aging kidney, nitric oxide (NO) availability is decreased. To investigate the role of NO in angiostatin production, human umbilical vein endothelial cells were treated with L-NG-nitroarginine methyl ester (L-NAME). L-NAME-treated cells showed increased cathepsin D activity and angiostatin production. For in vivo experiments, 16-to 18-month-old rats were treated with L-NAME or molsidomine for 3 months.

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