Phenotypic characteristics of diabetic kidney involvement

Abstract

Understanding phenotypic characteristics of the diabetic kidney is important for the development of therapies to prevent progression of diabetic nephropathy. In addition to glomerular hyperfiltration and kidney growth, major metabolic abnormalities characterize the diabetic kidney. Increased kidney oxygen consumption leads to cortical and medullary hypoxia in diabetes. Decreasing inspired oxygen to 10% reduces pO2, while oxygen consumption remains elevated, lactate increases, and redox potential decreases, but only in the diabetic kidney--a shift to Warburg metabolism.

Figure 1

In control and diabetic kidneys during normal inspired oxygen, or 20%, kidney oxygen consumption (Q_O2) is elevated in the diabetic kidneys, contributing to a reduced tissue pO₂ in the cortex of the kidney, 45 mmHg in control cortex and 35 mmHg in the cortex of diabetic kidneys. Lactate and pyruvate content and generation are normal, as is the redox potential in both control and diabetic kidneys. However, when inspired oxygen is reduced to 10%, control kidneys maintain normal oxidative metabolism and lactate and pyruvate levels remain constant, as does the redox potential, while cortical pO₂ fall further to 35 mmHg. However, in diabetic kidney tissue Q_O2 is maintained at the same levels while pO₂ falls further to 25 mmHg but lactate increases and pyruvate levels decrease in parallel with a marked reduction in NAD⁺/NADH ratio, a shift to Warburg metabolism. Why lower inspired pO₂ induces these changes is unknown but pO₂ levels should be decreased to levels comparable to diabetic kidneys to determine the effects on lactate and pyruvate generation.