Renal gluconeogenesis: axial and internephron heterogeneity and the effect of parathyroid hormone

To better understand the regulation of renal gluconeogenesis that occurs in the proximal nephron, glucose production rates from various substrates were determined in defined proximal tubule segments of the rat. Tubule segments tested were the S1 and S2 segments of superficial (SF) nephrons, the S1 segments of juxtamedullary (JM) nephrons, and the S3 segments. Glucose production (in decreasing order) was: from alpha-ketoglutarate, JM S1, SF S1, SF S2; from pyruvate, SF S2, JM S1, and SF S1; from glutamine, SF S1, JM S1; and from glutamate, SF S1 = JM S1. Little glucose was produced in the S3 segments. Glucose production from glutamate was lower than that from the other three substrates in JM S1, and glutamine was the best gluconeogenic substrate in SF S1. The effects of parathyroid hormone (PTH), a known stimulator of renal gluconeogenesis, and cAMP were examined using alpha-ketoglutarate as the substrate. Both stimulated glucose production in the S1 and S2 segments of the SF nephron. Although PTH stimulated adenylate cyclase in the S1 segments of the SF and JM nephrons, it had no effect on glucose production in the JM S1. Glucose production rose in the SF S1 and JM S1 in response to increasing concentrations of hydrogen or calcium ions, indicating that gluconeogenesis can be increased in these nephron segments. Differences may therefore be present in the cellular responses to PTH distal to cAMP formation in the nephron segments of the SF and JM nephrons. These findings show the presence of both axial and internephron heterogeneity of renal gluconeogenesis and suggest the difference in the effects of PTH on the function of SF and JM nephrons.