The Role of Renal Response to Amino Acid Infusion and Oral Protein Load in Normal Kidneys and Kidney With Acute and Chronic Disease

Francis B. Gabbai


Curr Opin Nephrol Hypertens. 2018;27(1):23-29. 

In This Article

Mechanisms Involved in the Renal Response to Protein Load or Amino Acid Infusion

Response to Individual Amino Acid Infusion

Intravenous infusion of glycine or arginine increases GFR. A similar response is not elicited by all amino acids as the infusion of nonbranched chain amino acids, such as valine, leucine, and isoleucine, do not modify GFR.[10] Although both glycine and arginine lead to robust increases in GFR in the order of 15–25%, the mechanism responsible is quite different.[11,12] Arginine infusion leads to renal and peripheral vasodilation.[13] Although nitric oxide generation constitutes a critical element of this response, arginine also induces mild increments in circulating insulin levels which are necessary but not sufficient to elicit this response.[12] It has been proposed that the increase in insulin levels promotes the entry of arginine into the caveoli and activation of the nitric oxide synthase.

In contrast with arginine, the vasodilatory response to glycine is mediated by the N-Methyl-D-Aspartate Glutamate receptor (NMDA-R).[14,15] The NMDA-R is a heterotetrameric amino acid receptor that functions as a membrane calcium channel and is localized in the subapical proximal tubule, Bowman capsule and mesangial cells.[14,15,16] Two L-glycine and two L-glutamate molecules lead to channel opening and calcium influx. Glutamate is a common amino acid in nature, and a major component of animal protein, such as meat, fish, milk, and cheese, or vegetable protein, such as mushroom and tomato.[17] Administration of an NMDA-R blocker or antagonist prevents the vasodilatory response to glycine.[14] Prior exposure to dietary protein simultaneously augments the vasodilatory response to intravenous glycine and increases renal NMDA-R protein expression.[18]

Monosodium glutamate (MSG) serves as flavoring in cooking to increase palatability and food selection in a meal, and as such, its consumption has increased worldwide. Mahieu et al.[16] have recently tested whether adding MSG (3 mg/kg/day) to a standard rat diet for a period of 16 weeks: alters the normal vasodilatory response to glycine; whether such response is modified by NMDA-R antagonist; and whether MSG treatment alters NMDA-R measurement using semiquantitative immunostaining. These studies demonstrate that chronic administration of MSG increases bGFR and reabsorption of sodium, potassium, and water. Glycine infusion elicits further increases in GFR demonstrating that high bGFR does not blunt RFR in these rats, and administration of the NMDA-R antagonist reduces the increase in GFR and RPF during glycine. MSG feeding produced an upregulation of the NMDA-R in proximal tubule, Bowman capsule and mesangial cells. Together these results reinforce the importance of the NMDA-R as an important mechanism to explain renal vasodilation in the setting of high protein intake. One could speculate that activity of this receptor may reset the value of bGFR.

Role of Glucagon, Arginine Vasopressin, and Urea

As described earlier, several humoral mediators have been proposed as mediators in the renal response to protein intake.[2,10–12] Among these are: insulin, nitric oxide, glucagon, and prostaglandins. To evaluate the role of these individual mediators, studies have focused on the effect of blockers of these mediators on the vasodilatory response to protein, or the ability of these individual mediators to induce a vasodilatory response similar to the one obtained during protein loading. Of interest, administration of these individual mediators alone has failed to reproduce an increase in GFR similar to a protein load suggesting that more than a single agent is necessary to obtain such a response. A recent review by Bankir et al.[19] elegantly demonstrates that not only glucagon and vasopressin are critical to this response, but generation of urea derived from amino acid metabolism also plays a critical role. Based on the information proposed by Bankir et al.[19] glucagon stimulates urea synthesis by the liver and its excretion by modifying its reabsorption in the thick ascending limb and collecting duct. Vasopressin allows concentration of urea and other associated protein waste products while conserving water. The combination of glucagon, vasopressin, and urea modify the composition of the fluid reaching the macula densa and, therefore, the activity of the tubuloglomerular feedback system critical to raise GFR (Table 1 and Figure 1).

Figure 1.

(Panel A) Depicts the changes in GFR and RPF in a normal healthy individual after an OPL or AA infusion. The combination of a large number of mediators is likely involved in this response. (Panel B). Absence of response to protein loading characterizes acute and chronic kidney injury and there is limited information regarding the mediators involved in the lack of response is AA, amino acid; GFR, glomerular filtration rate; NMDA, N-Methyl-D-Aspartate Glutamate; OPL, oral protein load; RPF, renal plasma flow.