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

Abstract

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.

Evidence that Alpha-1-Adrenergic Stimuli Specifically Increase Gluconeogenesis of the Isolated Proximal Convoluted Tubule in the Rat

“…There have been a few studies which reported direct measurement of newly syn thesized glucose using microdissected neph ron segments from rabbits [11. 12] and rats [13], In rabbits, a relatively high gluconeo genic activity was localized in PST [12], On the contrary, rat PCT revealed higher glucose production than PST, supporting earlier find ings of gluconeogenic enzyme localization in rat nephron segments [15]. Our results in this paper were quite consistent with these reports [13][14][15], Gluconeogenesis in the rat renal cortex can be stimulated by catecholamines [25][26][27], Studies with selective adrenergic agonists and antagonists have shown that this effect is mediated through an a-type of adrenoceptor rather than a (3-type [6,7], in which ajspecific agents were shown to be active in the metabolism using the apselective antagonist, thymoxamine, and the 012-selective antago nist, yohimbine [10], This finding was sup ported by the present study, demonstrating that ai-adrenergic stimuli specifically in crease renal gluconeogenesis dose-dependently ( fig.…”

“…On the other hand, it has already been reported that gluconeogenesis in the mam malian kidney is located almost exclusively in the proximal tubule according to direct anal ysis of glucose formation [11][12][13] or of glu coneogenic key enzymes such as phosphoenolpyruvate carboxykinase [14][15][16].…”

[14C]bicarbonate fixation into glucose and other metabolites in the liver of the starved rat under halothane anaesthesia. Metabolic channelling of mitochondrial oxaloacetate

“…This procedure gives a minimum S.R. of hepatic output for any assumed renal contribution to total gluconeogenesis, since Wang & Kurokawa (1984) have shown that all cortical cells use glutamine readily for gluconeogenesis and that in some it is a better precursor of glucose than is pyruvate. It is therefore likely that more of the renal glucose output came from glutamine than we have assumed, with consequent over-estimation of the S.R.…”

Post-transcriptional regulation of the Type IIA sodium-phosphate cotransporter by parathyroid hormone.

“…As shown in Figure 2, PTH regulates several ion transporters and metabolic pathways. PTH stimulates gluconeogenesis through the actions of adenylyl cyclase 66,67 , as well as ammoniagenesis through the increased catabolism of glutamate 68 . In the kidney, reabsorption of filtered bicarbonate is dependent on sodium-hydrogen exchange across the apical membrane of the proximal tubule, a process that is also decreased by PTH through the decreased expression and activity of the sodium/hydrogen exchanger isoform 3 (NHE3) 69,70 .…”