Role of carbonic anhydrase in acute recovery following renal ischemia reperfusion injury

Abstract

Ischemia reperfusion (IR) injury can cause acute kidney injury. It has previously been reported that kidney oxygen consumption (QO 2 ) in relation to glomerular filtration rate (GFR), and thus tubular sodium load, is markedly increased following IR injury, indicating reduced electrolyte transport efficiency. Since proximal tubular sodium reabsorption (TNa) is a major contributor to overall kidney QO 2 , we investigated whether inhibition of proximal tubular sodium transport through carbonic anhydrase (CA) inhibition would improve renal oxygenation following ischemia reperfusion. Anesthetized adult male Sprague Dawley rats were administered the CA inhibitor acetazolamide (50 mg/kg bolus iv), or volume-matched vehicle, and kidney function, hemodynamics and QO 2 were estimated before and after 45 minutes of unilateral complete warm renal ischemia. CA inhibition per se reduced GFR (-20%) and TNa (-22%), while it increased urine flow and urinary sodium excretion (36-fold). Renal blood flow was reduced (-31%) due to increased renal vascular resistance (+37%) without affecting QO 2 . IR per se resulted in similar decrease in GFR and TNa, independently of CA activity. However, the QO 2 /TNa ratio following ischemia-reperfusion was profoundly increased in the group receiving CA inhibition, indicating a significant contribution of basal oxygen metabolism to the total kidney QO 2 following inhibition of proximal tubular function after IR injury. Ischemia increased urinary excretion of kidney injury molecule-1, an effect that was unaffected by CA. In conclusion, this study demonstrates that CA inhibition further impairs renal oxygenation and does not protect tubular function in the acute phase following IR injury. Furthermore, these results indicate a major role of the proximal tubule in the acute recovery from an ischemic insult.

Modulation of Tubular pH by Acetazolamide in a Ca2+ Transport Deficient Mice Facilitates Calcium Nephrolithiasis

“…Importantly, in addition to urine alkalization, we used TRPC3 KO mice in this study because these mice are moderately hypercalciuric [ 18 ], a condition which is conducive for CaP stone formation. Acz was recently used in experimental models for ischemic reperfusion injury recovery, however its CA inhibition further impairs renal oxygenation [ 45 ]. Moreover, Acz has also been proposed as a treatment adjunct for patients with cystine and uric acid stone formation to standard alkalization therapy [ 46 ].…”

“…The observed differences in K + clearance particularly for the treated groups provide explanation for the observed increase in urinary pH among the treated groups. Studies have shown that, Acz results in increased Na + clearance which can be as a result of Acz’s inhibitory action on CA [ 45 , 52 ]. Similarly, Na + excretion is directly related to decrease in K + excretion which is associated with increasing serum K + levels [ 53 ].…”

Reducing Oxygen Demand to Alleviate Acute Kidney Injury

“…Rats were kept under general anesthesia throughout the experiment. Under this condition, they found that acetazolamide impaired renal oxygenation, increased oxygen consumption, and decreased GFR compared to vehicle-treated rats [108]. In small human trials, there is some evidence to suggest that acetazolamide ameliorates contrast-, cisplatin-, cardiopulmonary bypass-and rhabdomyolysis-induced AKI (Table 1) [62][63][64]109,110].…”

“…They found that acetazolamide reduced AKI by restoring renal blood flow, an effect that was associated with in-creased endothelial nitric oxide synthase (eNOS) activity, nitric oxide (NO) production, hypoxia inducible factor 1 subunit alpha (HIF-1α) expression, and decreased vascular permeability [107]. Conversely, Nensen et al [108] intravenously injected 50 mg/kg of acetazolamide into rats 45 minutes prior to clamping the renal pedicle for 45 minutes unilaterally and then allowed reperfusion for 2 hours. Rats were kept under general anesthesia throughout the experiment.…”