Adverse effects of α-ketoglutarate/malate in a rat model of acute kidney injury

Abstract

Acute kidney injury (AKI) is the most common kidney disease in hospitalized patients with high mortality. Ischemia and reperfusion (I/R) is one of the major causes of AKI. The combination of α-ketoglutarate+malate (αKG/MAL) showed the ability to reduce hypoxia-induced damage to isolated proximal tubules. The present study utilizes a rat model of I/R-induced AKI accompanied by intensive biomonitoring to examine whether αKG/MAL provides protection in vivo. AKI was induced in male Sprague-Dawley rats by bilateral renal clamping (40 min) followed by reperfusion (240 min). αKG/MAL was infused continuously for 60 min before and 45 min after ischemia. Normoxic and I/R control groups received 0.9% NaCl solution. The effect of αKG/MAL was evaluated by biomonitoring, blood and plasma parameters, histopathology, and immunohistochemical staining for kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), as well as by determination of tissue ATP and nonesterified fatty acid concentrations. Intravenous infusion of αKG/MAL at a cumulative dose of 1 mmol/kg each (146 mg/kg αKG and 134 mg/kg MAL) did not prevent I/R-induced increases in plasma creatinine, histopathological alterations, or cortical ATP depletion. On the contrary, the most notable adverse affect in animals receiving αKG/MAL was the decrease in mean arterial blood pressure, which was also accompanied by a reduction in heart rate. Supplementation with αKG/MAL, which is very protective against hypoxia-induced injury in isolated proximal tubules, does not protect against I/R-induced renal injury in vivo, possibly due to cardiovascular depressive effects.

The role of glycine in regulated cell death

“…Additionally, glycine has been reported to lower blood pressure in an NMDA-sensitive fashion [220]. Blood pressure is rarely measured in rodent AKI models, but can play a major role in the process and effects of administered metabolites on it [221]. …”

Resveratrol Does Not Protect from Ischemia-Induced Acute Kidney Injury in an in Vivo Rat Model

“…Destabilisation of blood pressure associated with bilateral (and not unilateral) renal ischemia has been described before [21, 22, 36], although to our knowledge studies performing close continuous arterial blood pressure monitoring especially during the clamping period have not been performed by other groups. The mechanisms involved in induction of hypotension during bilateral renal clamping remain unclear, but it is conceivable that this effect is related to interference by the clamping itself with sympathetic nerves surrounding the renal artery as decreasing blood pressure is observed immediately following mechanical manipulation.…”

“…As described previously [11, 21, 22] intravenous bolus injections of NaCl 0.9% were used to compensate for hypotension. Due to the low MAP in the context of bilateral renal clamping animals of both I/R RSV groups received numerous bolus injections during ischemia.…”

“…Anesthesia with isoflurane and analgesia with ketamine was performed as described previously [11, 21, 22]. A skin-deep incision was made along the thigh of the right hind limb after application of lidocaine (5 mg/kg s.c.).…”

“…RSV has been shown to lower systolic blood pressure in humans [20] and had adverse effects on blood pressure during reperfusion after severe intestinal ischemia in rats [11]. Hemodynamics is a vulnerable point in I/R-induced AKI [21, 22]. Therefore, in the present study a rat model of I/R-induced AKI equipped by intensive monitoring of vital parameters was utilized to examine whether intravenous application of solvent-free RSV provides direct renal protection in vivo .…”