SUMMARY The high renal oxygen (O2) demand is associated primarily with tubular O2 consumption (QO2) necessary for solute reabsorption. Increasing O2 delivery relative to demand via increased blood flow results in augmented tubular electrolyte load following elevated glomerular filtration, which, in turn, increases metabolic demand. Consequently, elevated kidney metabolism results in decreased tissue oxygen tension.The metabolic efficiency for solute transport (QO2/TNa) varies not only between different nephron sites, but also under different conditions of fluid homeostasis and disease. Contributing mechanisms include the presence of different Na+ transporters, different levels of oxidative stress and segmental tubular dysfunction.Sustained hyperglycaemia results in increased kidney QO2, partly due to mitochondrial dysfunction and reduced electrolyte transport efficiency. This results in intrarenal tissue hypoxia because the increased QO2 is not matched by a similar increase in O2 delivery.Hypertension leads to renal hypoxia, mediated by increased angiotensin receptor tonus and oxidative stress. Reduced uptake in the proximal tubule increases load to the thick ascending limb. There, the increased load is reabsorbed, but at greater O2 cost. The combination of hypertension, angiotensin II and oxidative stress initiates events leading to renal damage and reduced function.Tissue hypoxia is now recognized as a unifying pathway to chronic kidney disease. We have gained good knowledge about major changes in O2 metabolism occurring in diabetic and hypertensive kidneys. However, further efforts are needed to elucidate how these alterations can be prevented or reversed before translation into clinical practice.

IntroductionAt the onset of diabetes mellitus, the kidney begins to grow and GFR increases. Some time later, structural changes can occur in the glomerulus which form the basis for progressive diabetic nephropathy. Intrarenal hemodynamic abnormalities, as manifest by glomerular hyperfiltration, are thought to be among the foremost factors responsible for the onset and progression of diabetic glomerulopathy. To account for these hemodynamic abnormalities, investigators have characterized the functional effects of diabetes on the various segments of the glomerular microvasculature (reviewed in ref. 1), and many substances have been invoked as humoral mediators of vasodilation in the diabetic glomerulus (reviewed in ref.2). However, no single cause has emerged to account for glomerular hyperfiltration in diabetes. The principal idea behind the present study is that glomerular hyperfiltration in diabetes does not develop mainly because of disordered microvascular function or from imbalanced hormones impinging directly on the glomerulus. Instead, we propose that glomerular hyperfiltration results mainly from a primary increase in proximal tubular reabsorption which causes GFR to increase through the physiologic actions of tubuloglomerular feedback (TGF). Furthermore, we propose that this primary increase in reabsorption results, in good part, from hypertrophy of the tubule. This "tubular hypothesis" of diabetic hyperfiltration reverses the order of events as typically envisioned for the diabetic kidney, in which a primary reduction in vascular resistance causes GFR to increase and the tubule then grows larger in order to accommodate the increased filtered load.If the TGF response were slow enough, one could confirm the tubular hypothesis of glomerular hyperfiltration by recording a lag time between enlargement of the kidney and the onset of hyperfiltration. However, the time required for TGF to evoke a change in GFR is on the order of several seconds (3), whereas diabetic hypertrophy proceeds continuously over days. Therefore, a TGF-mediated cause and effect relationship between kidney size and GFR will not be revealed by their temporal relationship. In fact, the most that can be said of the temporal relationship between hyperfiltration and renal hypertrophy in human type I diabetes is that they both occur early (4). Similarly, in rats with diabetes induced by streptozotocin, kidney size (5), kidney protein/DNA ratio (6), and GFR all increase within 24 hours of the onset of diabetes, the latter notwith- In early diabetes, the kidney grows and the glomerular filtration rate (GFR) increases. This growth is linked to ornithine decarboxylase (ODC). The study of hyperfiltration has focused on microvascular abnormalities, but hyperfiltration may actually result from a prior increase in capacity for proximal reabsorption which reduces the signal for tubuloglomerular feedback (TGF). Experiments were performed in Wistar rats after 1 week of streptozotocin diabetes. Kidney weight, ODC activity, and GFR were correlated in diabe...

Excess NO generation plays a major role in the hypotension and systemic vasodilatation characteristic of sepsis. Yet the kidney response to sepsis is characterized by vasoconstriction resulting in renal dysfunction. We have examined the roles of inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) on the renal effects of lipopolysaccharide administration by comparing the effects of specific iNOS inhibition, L -N 6 -(1-iminoethyl)lysine (L-NIL), and 2,4-diamino-6-hydroxy-pyrimidine vs. nonspecific NOS inhibitors (nitro-L -arginine-methylester). cGMP responses to carbamylcholine (CCh) (stimulated, basal) and sodium nitroprusside in isolated glomeruli were used as indices of eNOS and guanylate cyclase (GC) activity, respectively. LPS significantly decreased blood pressure and GFR (112 Ϯ 4 vs. 83 Ϯ 4 mmHg; 2.66 Ϯ 0.29 vs. 0.96 Ϯ 0.22 ml/min, P Ͻ 0.05) and inhibited the cGMP response to CCh. GC activity was reciprocally increased. L-NIL and 2,4-diamino-6-hydroxy-pyrimidine administration prevented the decrease in GFR (2.71 Ϯ 0.28 and 3.16 Ϯ 0.18 ml/min, respectively), restored the normal response to CCh, and GC activity was normalized. In vitro application of L-NIL also restored CCh responses in LPS glomeruli. Neuronal NOS inhibitors verified that CCh responses reflected eNOS activity. L-NAME, a nonspecific inhibitor, worsened GFR (0.41 Ϯ 0.15 ml/min), a reduction that was functional and not related to glomerular thrombosis, and eliminated the CCh response. No differences were observed in eNOS mRNA expression among the experimental groups. Selective iNOS inhibition prevents reductions in GFR, whereas nonselective inhibition of NOS further decreases GFR. These findings suggest that the decrease in GFR after LPS is due to local inhibition of eNOS by iNOS, possibly via NO autoinhibition. ( J. Clin. Invest. 1997. 100:439-448.)

The proximal tubule of the kidney plays a crucial role in the renal handling of drugs (e.g., diuretics), uremic toxins (e.g., indoxyl sulfate), environmental toxins (e.g., mercury, aristolochic acid), metabolites (e.g., uric acid), dietary compounds, and signaling molecules. This process is dependent on many multispecific transporters of the solute carrier (SLC) superfamily, including organic anion transporter (OAT) and organic cation transporter (OCT) subfamilies, and the ATP-binding cassette (ABC) superfamily. We review the basic physiology of these SLC and ABC transporters, many of which are often called drug transporters. With an emphasis on OAT1 (SLC22A6), the closely related OAT3 (SLC22A8), and OCT2 (SLC22A2), we explore the implications of recent in vitro, in vivo, and clinical data pertinent to the kidney. The analysis of murine knockouts has revealed a key role for these transporters in the renal handling not only of drugs and toxins but also of gut microbiome products, as well as liverderived phase 1 and phase 2 metabolites, including putative uremic toxins (among other molecules of metabolic and clinical importance). Functional activity of these transporters (and polymorphisms affecting it) plays a key role in drug handling and nephrotoxicity. These transporters may also play a role in remote sensing and signaling, as part of a versatile small molecule communication network operative throughout the body in normal and diseased states, such as AKI and CKD.

A B S T R A CT The effects of both synthetic and biologically produced angiotensin II (AII) upon the process of glomerular filtration were examined in the plasma-expanded (2.5% body wt) Munich-Wistar rat, by micropuncture evaluation of pressures, nephron plasma flow (rpf) and filtration rate (sngfr). Plasma expansion was chosen as a control condition because (a) response to AII was uniform and predictable, (b) endogenous generation of AII was presumably suppressed, and (c) the high control values for rpf permitted accurate determination of values for the glomerular permeability coefficient (LPA) before and during AII infusion. With subpressor quantities of synthetic Asn-1, Val-5 AII (< 5 ng/100 g body wt/min), sngfr fell from 47.7 in the control group to 39.8 nl/min/g kidney (P < 0.005). The rpf fell to 60% of control values (P < 0.001). Measurement of glomerular capillary (Pa) and Bowman's space (P.) hydrostatic pressures in surface glomeruli with a servo-nulling device permitted evaluation of the hydrostatic pressure gradient (AP = Pa-P0). AP increased from 38.1+±1.2 in control to 45.9±1.3 mm Hg after Asn-1, Val-5 AII and essentially neutralized the effect of decreased rpf in sngfr. The sngfr then fell as a result of a decrease in LPA from 0.063+0.008 in control to 0.028±0.004 nl/s/g kidney/mm Hg after Asn-1, Val-5 AII (P < 0.02).Lower doses of Asp-1, Ile-5 AII (< 3 ng/100 g body wt/min) had no effect on sngfr, rpf, AP, and afferent and efferent vascular resistance, but significantly elevated systemic blood pressure, suggesting peripheral ef- fects on smooth muscle at this low dose. LPA was 0.044+ 0.007 nl/s/g kidney/mm Hg after low-dose Asp-1, Ile-5 AII, and 0.063±0.008 in the control group (0.2 > P > 0.1). Higher, equally pressor doses of native AII (5 ng/ 100 g body wt/min) produced effects almost identical to similar quantites of synthetic Asn-1, Val-5 AII upon rpf, AP, sngfr, and renal vascular resistance. LPA again fell to 0.026±0.004 nl/s/g kidney/mm Hg, a value almost identical to that after the synthetic AI. Paired studies with Asp-1, Ile-5 AII also demonstrated a consistent reduction in LPA.Both synthetic (Asn-1, Val-5 AII) and native AII (Asp-1, Ile-5 AII) produce a reduction in LpA, presumably by direct action on the glomerular capillary or mesangium, where no smooth muscle cells are present. Although quantitative differences in peripheral vascular effects of the two forms of AII are demonstrated, the effects on LPA occur at similar doses of both agents in the plasma-expanded rat. A third major physiologic action for AII is postulated that requires an effector cell in the glomerulus that differs from those previously demonstrated for vascular smooth muscle and the adrenal glomerulosa.

At the onset of diabetes mellitus, the glomerular filtration rate becomes supranormal. Discovery science has identified many abnormalities in the early diabetic kidney that apparently contribute to this phenotype. A serviceable understanding of the early diabetic kidney requires this information to fit together. It is the purpose of this article to present an archetype that explains multiple nuances of kidney function in early diabetes. We refer to this archetype as the "tubular hypothesis of glomerular filtration." Its basic tenet is that strange effects of diabetes on glomerular filtration stem from primary effects on the proximal tubule or loop of Henle that impact glomerular filtration by feedback through the macula densa. This theory can explain diabetic hyperfiltration, a paradoxical effect of dietary salt on glomerular filtration rate in diabetes, and the renal response to dietary protein and amino acid infusion in diabetes. The discussion centers on the kidney as an integrated system of parts rather than on the specific cellular mechanisms that comprise those parts.

Nitric oxide (NO) has been proposed to modulate the renal response to protein as well as basal renal hemodynamics. We investigated whether NO and angiotensin II (AII) interact to control glomerular hemodynamics and absolute proximal tubular reabsorption (APR) during glycine infusion and in unstimulated conditions. In control rats, glycine increased single nephron GFR and plasma flow with no change in APR. The NO synthase blocker, NG-monomethyl L-arginine (LNMMA), abolished the vasodilatory response to glycine, possibly through activation of tubuloglomerular feedback due to a decrease in APR produced by LNMMA + glycine. Pretreatment with an AII receptor antagonist, DuP 753, normalized the response to glycine at both glomerular and tubular levels. In unstimulated conditions, LNMMA produced glomerular arteriolar vasoconstriction, decreased the glomerular ultrafiltration coefficient, and reduced single nephron GFR. These changes were associated with a striking decrease in APR. DuP 753 prevented both glomerular and tubular changes induced by LNMMA. In conclusion, NO represents a physiological antagonist of AII at both the glomerulus and tubule in both the basal state and during glycine infusion; and inhibition of NO apparently enhances or uncovers the inhibitory effect of AII on proximal reabsorption.

Polyamines are required for entry and progression of the cell cycle. As such, augmentation of polyamine levels is essential for cellular transformation. Polyamines are autoregulated through induction of antizyme, which represses both the rate-limiting polyamine biosynthetic enzyme ornithine decarboxylase and cellular polyamine transport. In the present study we demonstrate that agmatine, a metabolite of arginine via arginine decarboxylase (an arginine pathway distinct from that of the classical polyamines), also serves the dual regulatory functions of suppressing polyamine biosynthesis and cellular polyamine uptake through induction of antizyme. The capacity of agmatine to induce antizyme is demonstrated by: (a) an agmatine-dependent translational frameshift of antizyme mRNA to produce a fulllength protein and (b) suppression of agmatine-dependent inhibitory activity by either anti-antizyme IgG or antizyme inhibitor. Furthermore, agmatine administration depletes intracellular polyamine levels to suppress cellular proliferation in a transformed cell line. This suppression is reversible with polyamine supplementation. We propose a novel regulatory pathway in which agmatine acts as an antiproliferative molecule and potential tumor suppressor by restricting the cellular polyamine supply required to support growth.Polyamines (putrescine, spermidine, and spermine) are required for DNA replication, proliferation, and cell homeostasis (1-3). Ornithine decarboxylase (ODC) 1 is the first rate-limiting enzyme of polyamine biosynthesis and one of the most highly regulated eukaryotic enzymes. Cellular polyamine transporters are stimulated by many of the same factors that induce ODC activity, and similarly, enhanced cellular polyamine uptake occurs both in normal but rapidly proliferating cells (4) and in tumor cell lines (5-8). Cells in vivo can acquire polyamines released into the circulation by other cells, dietary sources, and gut flora. Polyamines have been demonstrated to play an important role in the transformation process. Conversely, polyamine depletion results in growth arrest (9, 10).Intracellular polyamine concentrations are autoregulated by the induction of the protein antizyme (11). Antizyme is the only known endogenous protein that binds to ODC, inhibiting activity and accelerating its degradation (12). In addition to inhibiting polyamine biosynthesis, antizyme has recently been shown to concurrently suppress polyamine transporter(s) (13,14). Pharmacological inhibition of ODC activity, however, has been shown to result in compensatory cellular polyamine uptake (6). Beneficial therapeutic intervention must therefore address both polyamine transport as well as biosynthesis (for review see Ref. 15).The metabolism of arginine to agmatine by ADC has only recently been demonstrated in mammals (16). As agmatine and polyamines are structurally analogous polycationic molecules derived from distinct arginine-dependent pathways (6), we speculated that the ADC metabolite agmatine may play a role in regulating intracellul...