Impacts of nitric oxide and superoxide on renal medullary oxygen transport and urine concentration

Abstract

The goal of this study was to investigate the reciprocal interactions among oxygen (O2), nitric oxide (NO), and superoxide (O2 (-)) and their effects on medullary oxygenation and urinary output. To accomplish that goal, we developed a detailed mathematical model of solute transport in the renal medulla of the rat kidney. The model represents the radial organization of the renal tubules and vessels, which centers around the vascular bundles in the outer medulla and around clusters of collecting ducts in the inner medulla. Model simulations yield significant radial gradients in interstitial fluid oxygen tension (Po2) and NO and O2 (-) concentration in the OM and upper IM. In the deep inner medulla, interstitial fluid concentrations become much more homogeneous, as the radial organization of tubules and vessels is not distinguishable. The model further predicts that due to the nonlinear interactions among O2, NO, and O2 (-), the effects of NO and O2 (-) on sodium transport, osmolality, and medullary oxygenation cannot be gleaned by considering each solute's effect in isolation. An additional simulation suggests that a sufficiently large reduction in tubular transport efficiency may be the key contributing factor, more so than oxidative stress alone, to hypertension-induced medullary hypoxia. Moreover, model predictions suggest that urine Po2 could serve as a biomarker for medullary hypoxia and a predictor of the risk for hospital-acquired acute kidney injury.

Keywords: hypoxia; mathematical model; oxygen; sodium transport.

Fig. 1.

Schematic diagram of a cross section through the outer stripe, inner stripe, upper inner medulla (IM), mid-IM, and deep IM, showing interstitial regions (R1, R2, R3, and R4) and relative positions of tubules and vessels. Decimal numbers indicate relative interaction weightings with regions [e.g., in the outer stripe, half of the short descending vasa recta (SDV) lie in R1, and half lie in R2]. CD, collecting duct; LDV, long descending vas rectum; AVRs, populations of ascending vasa recta; SDL/SAL, descending/ascending limbs of short loops of Henle; LDL/LAL, descending/ascending limbs of long loops of Henle. Subscript “S,” “M,” and “L” associated with a LAL denotes limbs that turn with the first mm of the IM (S), within the mid-IM (M), or reach into the deep IM (L). Dotted-line box in deep IM indicates that LDV, LDL, LAL, and CD are weighted evenly between the 4 regions. Tubules, vessels, and interstitium are denoted in blue, red, and pink, respectively.

Fig. 2.

Region Po₂ (mmHg) vs. depth (cm) in the 6 cases. A: base case. B: g_active,NO = 1. C: $h_{\text{active,}{\text{O}}_2^{-}}$ = 0.7. D: g_active,NO = 1 and $h_{\text{active,}{\text{O}}_2^{-}}$ = 0.7. E: DVR inflow 12 nl/min. F: DVR inflow 6 nl/min. Outer medullary (OM)/IM boundary at 0.2 cm.

Fig. 3.

Region NO concentration (nM) vs. depth (cm) in the 6 cases. A: base case. B: g_active,NO = 1. C: $h_{\text{active,}{\text{O}}_2^{-}}$ = 0.7. D: g_active,NO = 1 and $h_{\text{active,}{\text{O}}_2^{-}}$ = 0.7. E: DVR inflow 12 nl/min. F: DVR inflow 6 nl/min. OM/IM boundary at 0.2 cm.

Fig. 4.

Region O₂⁻ concentration (nM) vs. depth (cm) in the 6 cases. A: base case. B: g_active,NO = 1. C: $h_{\text{active,}{\text{O}}_2^{-}}$ = 0.7. D: g_active,NO = 1 and $h_{\text{active,}{\text{O}}_2^{-}}$ = 0.7. E: DVR inflow 12 nl/min. F: DVR inflow 6 nl/min. OM/IM boundary at 0.2 cm.

Fig. 5.

Effective ascending limb V_max (A), effective CD V_max (B), and R4 Po₂ (C) vs. depth for superficial single nephron glomerular filtration rates (SNGFRs) of 24, 30 (base case), 36, and 42 nl/min.

Fig. 6.

Feedback loop outlining the effects of O₂, NO, and O₂⁻ on active NaCl transport rate. Solid lines indicate effects on production rate, dashed lines indicate effects on consumption rate, and dotted lines indicate effects on active NaCl transport rate (T_Na). Arrows at the ends of lines indicate stimulation (or increase), whereas circles at the ends of lines indicate inhibition (or decrease).

Fig. 7.

Average R4 inner stripe Po₂ in the base case and under hypertensive conditions.

Fig. 8.

Urine Po₂ vs. average inner stripe short ascending limb (IS SAL) Po₂ (mmHg) for all cases in results. Numbers (1–14) correspond to those listed in Table 3 (e.g., marker “9” in figure corresponds to the urine Po₂ and average inner stripe short ascending limb Po₂ in the “DVR inflow = 12 nl/min” simulation).