Role of 2′,3′-cyclic nucleotide 3′-phosphodiesterase in the renal 2′,3′-cAMP-adenosine pathway

Jackson, Edwin K.; Gillespie, Delbert G.; Mi, Zaichuan; Cheng, Dongmei; Bansal, Rashmi; Janesko‐Feldman, Keri; Kochanek, Patrick M.

doi:10.1152/ajprenal.00134.2014

Cited by 15 publications

(12 citation statements)

References 55 publications

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“…18 Finally, we observed that, in CNPase +/+ kidneys, energy depletion increases kidney tissue levels of 29,39-cAMP in CNPase 2/2 but not CNPase +/+ kidneys. 18 These findings support the view that kidneys express CNPase and that renal CNPase mediates, in part, the renal metabolism of 29,39-cAMP.…”

Section: Discussionmentioning

confidence: 51%

“…18 Moreover, we found that overexpression of CNPase in kidney cells increases the metabolism of exogenous 29,39-cAMP to 29-AMP and that infusions of 29,39-cAMP into CNPase +/+ kidneys increase renal venous 29-AMP, and this response is diminished in CNPase 2/2 kidneys. 18 Finally, we observed that, in CNPase +/+ kidneys, energy depletion increases kidney tissue levels of 29,39-cAMP in CNPase 2/2 but not CNPase +/+ kidneys. 18 These findings support the view that kidneys express CNPase and that renal CNPase mediates, in part, the renal metabolism of 29,39-cAMP.…”

Section: Discussionmentioning

confidence: 76%

“…Although CNPase is considered primarily a brain protein, we previously investigated whether CNPase participates in the renal metabolism of 29,39-cAMP. 18 We observed that CNPase mRNA and protein exist in rat glomerular mesangial, preglomerular vascular smooth muscle, and endothelial cells as well as in proximal tubular, thick ascending limb, and collecting duct cells. 18 Moreover, we found that overexpression of CNPase in kidney cells increases the metabolism of exogenous 29,39-cAMP to 29-AMP and that infusions of 29,39-cAMP into CNPase +/+ kidneys increase renal venous 29-AMP, and this response is diminished in CNPase 2/2 kidneys.…”

Section: Discussionmentioning

confidence: 80%

“…18 We observed that CNPase mRNA and protein exist in rat glomerular mesangial, preglomerular vascular smooth muscle, and endothelial cells as well as in proximal tubular, thick ascending limb, and collecting duct cells. 18 Moreover, we found that overexpression of CNPase in kidney cells increases the metabolism of exogenous 29,39-cAMP to 29-AMP and that infusions of 29,39-cAMP into CNPase +/+ kidneys increase renal venous 29-AMP, and this response is diminished in CNPase 2/2 kidneys. 18 Finally, we observed that, in CNPase +/+ kidneys, energy depletion increases kidney tissue levels of 29,39-cAMP in CNPase 2/2 but not CNPase +/+ kidneys.…”

Section: Discussionmentioning

confidence: 80%

“…Our recent studies identify 29,39-cyclic nucleotide 39-phosphodiesterase (CNPase) as an important enzyme mediating the renal metabolism of 29,39-cAMP to 29-AMP. 18 Thus, it is conceivable that inhibition of CNPase augments renal autophagy and protects against ischemia-reperfusion (IR) -induced AKI. In this study, we test this hypothesis by comparing renal functional and structural outcomes, mitochondrial function, number and area, and autophagy in CNPase knockout (KO; CNPase 2/2 ) versus wild-type (CNPase +/+ ) mice subjected to renal IR-induced AKI.…”

mentioning

confidence: 99%

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

Jackson

Menshikova

et al. 2015

JASN

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A positional isomer of 39,59-cAMP, 29,39-cAMP, is produced by kidneys in response to energy depletion, and renal 29,39-cyclic nucleotide 39-phosphodiesterase (CNPase) metabolizes 29,39-cAMP to 29-AMP; 29,39-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 2/2 ) 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 29,39-cAMP to 29-AMP in CNPase 2/2 mice. Neither genotype nor IR affected BP, heart rate, urine volume, or albumin excretion. In WT mice, renal IR reduced 14 C-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 2/2 mice. Histologic analysis revealed that IR induced severe damage in kidneys from WT mice, whereas histologic changes were minimal after IR in CNPase 2/2 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 2/2 mice. We conclude that CNPase deletion attenuates IR-induced AKI, in part by accelerating autophagy with targeted removal of damaged mitochondria. In response to energy depletion, rat 1,2 and mouse 3 kidneys produce 29,39-cAMP, a positional isomer of 39,59-cAMP that is generated when mRNA is enzymatically degraded. 2 A study by Azarashvili et al. 4 shows that 29,39-cAMP is a potent opener of mitochondrial permeability transition pores (mPTPs).Opening of mPTPs causes mitochondria damage, 5 and mitochondrial damage is a stimulus for autophagy. [6][7][8] Renal autophagy protects against AKI, [9][10][11][12][13][14][15][16] and insufficient autophagy contributes to organ failure. 17 Therefore, it is conceivable that 29,39-cAMP, by increasing autophagy, protects against AKI. Our recent studies identify 29,39-cyclic nucleotide 39-phosphodiesterase (CNPase) as an important enzyme mediating the renal metabolism of

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 80%

mentioning

confidence: 99%

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

Jackson

Menshikova

et al. 2015

JASN

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Discovery and Roles of 2′,3′-cAMP in Biological Systems

Jackson

2015

Handbook of Experimental Pharmacology

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In 2009, investigators using ultra-performance liquid chromatography-tandem mass spectrometry to measure, by selected reaction monitoring, 3',5'-cAMP in the renal venous perfusate from isolated, perfused kidneys detected a large signal at the same m/z transition (330 → 136) as 3',5'-cAMP but at a different retention time. Follow-up experiments demonstrated that this signal was due to a positional isomer of 3',5'-cAMP, namely, 2',3'-cAMP. Soon thereafter, investigative teams reported the detection of 2',3'-cAMP and other 2',3'-cNMPs (2',3'-cGMP, 2',3'-cCMP, and 2',3'-cUMP) in biological systems ranging from bacteria to plants to animals to humans. Injury appears to be the major stimulus for the release of these unique noncanonical cNMPs, which likely are formed by the breakdown of RNA. In mammalian cells in culture, in intact rat and mouse kidneys, and in mouse brains in vivo, 2',3'-cAMP is metabolized to 2'-AMP and 3'-AMP; and these AMPs are subsequently converted to adenosine. In rat and mouse kidneys and mouse brains, injury releases 2',3'-cAMP, 2'-AMP, and 3'-AMP into the extracellular compartment; and in humans, traumatic brain injury is associated with large increases in 2',3'-cAMP, 2'-AMP, 3'-AMP, and adenosine in the cerebrospinal fluid. These findings motivate the extracellular 2',3'-cAMP-adenosine pathway hypothesis: intracellular production of 2',3'-cAMP → export of 2',3'-cAMP → extracellular metabolism of 2',3'-cAMP to 2'-AMP and 3'-AMP → extracellular metabolism of 2'-AMP and 3'-AMP to adenosine. Since 2',3'-cAMP has been shown to activate mitochondrial permeability transition pores (mPTPs) leading to apoptosis and necrosis and since adenosine is generally tissue protective, the extracellular 2',3'-cAMP-adenosine pathway may be a protective mechanism [i.e., removes 2',3'-cAMP (an intracellular toxin) and forms adenosine (a tissue protectant)]. This appears to be the case in the brain where deficiency in CNPase (the enzyme that metabolizes 2',3'-cAMP to 2-AMP) leads to increased susceptibility to brain injury and neurological diseases. Surprisingly, CNPase deficiency in the kidney actually protects against acute kidney injury, perhaps by preventing the formation of 2'-AMP (which turns out to be a renal vasoconstrictor) and by augmenting the mitophagy of damaged mitochondria. With regard to 2',3'-cNMPs and their downstream metabolites, there is no doubt much more to be discovered.

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2′,3′-Cyclic Mononucleotide Metabolism and Possible Roles in Bacterial Physiology

Fontaine

Duggal

Weinert

2020

Microbial Cyclic Di-Nucleotide Signaling

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Role of 2′,3′-cyclic nucleotide 3′-phosphodiesterase in the renal 2′,3′-cAMP-adenosine pathway

Cited by 15 publications

References 55 publications

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

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

Discovery and Roles of 2′,3′-cAMP in Biological Systems

2′,3′-Cyclic Mononucleotide Metabolism and Possible Roles in Bacterial Physiology

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