Exogenous adenosine triphosphate (ATP) preserves proximal tubule microfilament structure and function in vivo in a maleic acid model of ATP depletion.

Abstract

The hallmark of ischemic acute renal failure is a rapid and early decline in proximal tubule ATP. Since we have previously shown that over half of apical microfilament losses occur within the first 5 min of experimental ischemic injury, we postulated that microfilament (F-actin) structure and cellular location are dependent on cellular ATP levels. To test this hypothesis, we used maleic acid to selectively inhibit renal cortical ATP production in vivo. Maleic acid significantly decreased tissue ATP and apical F-actin in a dose-dependent manner relative to equimolar sodium chloride controls, yet higher doses of maleic acid quantitatively resulted in net actin polymerization, primarily in the cytoplasm. Functionally, maleic acid decreased glomerular filtration rate (GFR) and tubular reabsorption of sodium (TRN.) in a dose-dependent manner relative to sodium chloride controls. Administration of exogenous ATP resulted in significant increases in tissue ATP, net actin depolymerization, and relocation of F-actin from the cytoplasm back to the apical surface coinciding with increases in GFR and TRN,. Thus, ATP depletion induced by maleic acid resulted in significant cytoskeletal and functional alterations that were ameliorated by exogenous ATP. We therefore conclude that the structure and cellular location of F-actin necessary for normal functioning of proximal tubule cells in vivo is dependent on tissue ATP levels. (J.

HMG–CoA Reductase Activation and Urinary Pellet Cholesterol Elevations in Acute Kidney Injury

“…If so, such a finding might have potential value as a "biomarker" of AKI. To gain some initial experimental support for this hypothesis, we collected urine samples from mice that had been subjected to two experimental models of AKI: glycerol induced rhabdomyolyis (17,18) or the maleate model (ATP depletion induced) of ARF (19,20). Urine samples were collected at either 3 or 24 hours post-AKI induction, and, after centrifugation, the pellets were extracted in chloroform: methanol and assayed for cholesterol content (21,22).…”

Maleate nephrotoxicity: mechanisms of injury and correlates with ischemic/hypoxic tubular cell death

“…When injected into rodents, maleic acid undergoes relatively selective proximal tubule (PT) cell uptake via organic anion transporters (OATs) (9,10,30). Once intracellular accumulation occurs, maleate is a preferred substrate for succinyl-CoA: 3-oxoacid CoA transferase (SCOTase) (24 -26, 32).…”

“…Ample levels of CoA are essential for fatty acid "activation," allowing for their subsequent metabolism through the Krebs cycle, yielding ATP. In the absence of this process, PT ATP depletion and cell injury result (10,23). Additionally, maleate conjugates the sulfhydryl group of glutathione (GSH) (19,23), culminating in GSH depletion and potential oxidant tubular stress (20,27,33).…”

“…Additionally, maleate conjugates the sulfhydryl group of glutathione (GSH) (19,23), culminating in GSH depletion and potential oxidant tubular stress (20,27,33). Depending on the severity of these processes, either functional transport defects (Fanconi syndrome) or proximal tubular necrosis/filtration failure result (3,10,13).…”

“…This is likely because no direct clinical equivalent of maleate toxicity exists (in sharp contrast to widely employed ARF models such as glycerol-induced rhabdomyolysis, aminoglycoside nephrotoxicity, or cisplatin-induced ARF). Despite the lack of a direct clinical correlate, the maleate model has theoretical appeal because it can induce dose-dependent, PT-specific, ATP and GSH depletion (8,10). Thus we hypothesized that it might represent a useful and underutilized ARF model that can simulate selected components of the ischemic tubular injury cascade.…”