Altered renal intermediary metabolism and the onset of renal dysfunction in the streptozotocin-diabetic rat
The present studies investigated the relationship between altered renal carbohydrate intermediary metabolism and kidney functional and structural changes in the adult Spraque-Dawley rat. Both the acute (upto 28 days) and chronic (60-120 days) diabetic states were invstigated. The single intraperitoneal injection of streptozotocin at a dose of 45mg/kg body weight produced a stable, non-ketotic, non-insulin dependent and reproducible diabetic state. Compared to age matched control animals (AMC), diabetic animals (DA) demonstrated a progressive increase in mean UFR, plasma glucose, creatinine, glycosuria values and urea clearance rate over the experimental course while creatinine clearance (CCR) fell from day 21 onwards reaching 50% of AMC values by day 120. Changes in renal and hepatic metabolite concentrations were apparent after 4 days of diabetes and two patterns emerged. Renal and hepatic glucose, glocuse-1-phosphate and β-hydroxybutyric acid concentrations progressively increased over the 120 days experimental period while reduced concentrations of glycolytic and other metabolic intermediates, namely, glucose-60-phosphate, fructose-6-phosphate, fructose-1,6-bisphosphate, glyceraldehyde-3-phosphate, dihydroxyacetone 3- phosphate and malonyl-CoA concentrations were present. Increased concentrations of BHBA in both the liver and kidney was accompanied by the progressive reduction of malonyl-CoA. Since gluconeognesis is favoured at the expense of glycolysis in these diabetic animals, the absence of phosphofructokinase activity may be explained by a decreased concentration of fructose-6-phosphate. Renal gluconeogenic enzymes such as fructose-1,6-phosphatase were mainly located in the kidney cortex, predominantly located in the proximal tubular epithelium and that glycolytic enzymes such as hexokinase occurred mainly in the kidney medulla, restricted essentially in distal segments. Histological examination demonstrated an increasing degree of renal clear cell changes affecting from 5-20% of cells noted from day 10 to day 120, respectively in the cortical renal tubules. In addition acute pyelonephritis was also observed in all diabetic animals on days 90 and 120.