Regulation of kidney function and metabolism: a question of supply and demand

Abstract

Kidney blood flow and glomerular filtration rate (GFR) are maintained relatively constant by hormonal influences and by efficient autoregulation. However, the kidney remains at risk for ischemia and acute kidney injury. Increases in kidney blood flow cause parallel increments in GFR, thereby dictating tubular reabsorption and increased oxygen/metabolic demands. Coordination between kidney blood flow and GFR with tubular reabsorption is maintained by the tubuloglomerular feedback (TGF) system whereby delivery of NaCl to the macula densa varies inversely with nephron GFR. Metabolic products, ATP and adenosine, are the mediators of TGF via afferent arteriolar vasoconstriction, and nitric oxide; COX-2 products and angiotensin II are modulators of acute TGF responses and temporal adaptation of TGF. Oxygen requirements and metabolic efficiency of Na transport in the kidney are significant variables that are regulated by both mediators and modulators of TGF. These metabolic and hormonal substances efficiently regulate both kidney supply and demand.

Fig. 1

Schematic operation of the tubuloglomerular feedback system (TGF). Increases in delivery and reabsorption of NaCl at the macula densa cell elicits vasoconstriction of the afferent arteriole resulting in a reduction of renal blood flow and the glomerular hydrostatic pressure as well as reductions in the glomerular ultrafiltration coefficient, K_f. The net effect of this TGF response is to reduce glomerular filtration rate. This reduction constitutes a negative feedback system which returns tubular fluid delivery and reabsorption of NaCl at the macula densa to control levels. The net effect of this TGF system is to stabilize late proximal flow rate, augment autoregulation of renal blood flow (RBF) and prevent major urinary losses of NaCl and water by overwhelming distal tubular reabsorptive capacities.

Fig. 2

The signal transduction mechanism for transmission of the macula densa tubuloglomerular feedback signal to the afferent arteriole and glomerulus. Increased delivery of fluid to the macula densa promotes increased NaCl reabsorption. NaCl reabsorption causes the immediate release of ATP, which is degraded extracellularly to AMP and, specifically, further degraded by ecto-5′-nucleotidase (e-5′-NT) and to adenosine, a substance which is a vasoconstrictor at the afferent arteriole. Increased NaCl reabsorption in the macula densa cell also causes generation of nitric oxide and may release prostaglandins via COX-2. In addition to acting as primary vasodilators which counteract the effects of adenosine and ATP, NO also inhibits e-5′-NT thereby reducing the generation of adenosine. NaCl transport at the macula densa also modifies the generation of angiotensin II (AII) via renin. NO and COX-2 are also modulators of AII generation. ATP and adenosine mediators of the acute tubuloglomerular feedback response, and NO, prostaglandins from COX-2, and AII are further modulators of the tubuloglomerular feedback response and contribute to resetting or adaptation of tubuloglomerular feedback.

Fig. 3

Effects of NO and NOS-1 blockers on oxygen consumption in freshly harvested isolated proximal tubules. Panel A demonstrates the profile of declining O2 % in a metabolic chamber containing proximal tubules. When the NOS-1 inhibitor, SMTC, is added, oxygen consumption increases, designated by the increase in slope of decline. When an NO donor, NONOate is applied, oxygen consumption decreases dramatically. In Panel B absolute oxygen consumption is depicted in control tubules and after SMTC, the NOS-1 blocker. The increase in oxygen consumption after NOS-1 blockade is totally reversed by application of the NO donor, suggesting NO specificity to the phenomenon. These data suggest a major role for intracellular NOS activity in regulation of oxygen consumption, probably at the mitochondrial level.

Fig. 4

The hormonal control of kidney oxygen supply and demand: Prevention of ischemia. Both oxygen and substrate supply and oxygen and substrate utilization or demand are controlled by a variety of hormonal and metabolic factors. There is a general pattern that substances which decrease supply tend to increase demand at the level of tubular epithelium, either by increasing reabsorption or increasing oxygen required for sodium transport. Such a relationship is logical from the standpoint of evolutionary biology in that metabolic and hormonal regulators will modify both supply and demand. The balance of these forces determines the threshold of kidney ischemia.