Renal 2′,3′-Cyclic Nucleotide 3′-Phosphodiesterase Is an Important Determinant of AKI Severity after Ischemia-Reperfusion

[摘要] A positional isomer of 3′,5′-cAMP, 2′,3′-cAMP, is produced by kidneys in response to energy depletion, and renal 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) metabolizes 2′,3′-cAMP to 2′-AMP; 2′,3′-cAMP is a potent opener of mitochondrial permeability transition pores (mPTPs), which can stimulate autophagy. Because autophagy protects against AKI, it is conceivable that inhibition of CNPase protects against ischemia-reperfusion (IR) –induced AKI. Therefore, we investigated renal outcomes, mitochondrial function, number, area, and autophagy in CNPase-knockout (CNPase−/−) versus wild-type (WT) mice using a unique two–kidney, hanging–weight model of renal bilateral IR (20 minutes of ischemia followed by 48 hours of reperfusion). Analysis of urinary purines showed attenuated metabolism of 2′,3′-cAMP to 2′-AMP in CNPase−/− mice. Neither genotype nor IR affected BP, heart rate, urine volume, or albumin excretion. In WT mice, renal IR reduced 14C-inulin clearance (index of GFR) and increased renal vascular resistance (measured by transit time nanoprobes) and urinary excretion of kidney injury molecule-1 and neutrophil gelatinase–associated lipocalin. IR did not affect these parameters in CNPase−/− mice. Histologic analysis revealed that IR induced severe damage in kidneys from WT mice, whereas histologic changes were minimal after IR in CNPase−/− mice. Measurements of renal cardiolipin levels, citrate synthase activity, rotenone–sensitive NADH oxidase activity, and proximal tubular mitochondrial and autophagosome area and number (by transmission electron microscopy) indicted accelerated autophagy/mitophagy in injured CNPase−/− mice. We conclude that CNPase deletion attenuates IR-induced AKI, in part by accelerating autophagy with targeted removal of damaged mitochondria.

[学科分类] 泌尿医学