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Relation of adenosine to medullary injury in the perfused rat kidney
F H Epstein1, S Rosen, G Galicka-Piskorska
1Department of Medicine and Pathology, Harvard Medical School, Boston, Mass.
Abstract:
In isolated perfused rat kidneys the medullary thick ascending limb (mTAL) is uniquely vulnerable to cellular injury produced by its hypoxic milieu and exacerbated by active transport. Endogenous inhibitors of transport might therefore be expected to reduce cell injury. We studied the possible role of adenosine in altering mTAL damage in isolated rat kidneys perfused for 60 min. When adenosine deaminase was added to the recirculating perfusate in 8 experiments, severe damage to mTAL cells adjacent to the inner medulla was significantly exacerbated to involve 89.4 +/- 3% of them as compared to 74.9 +/- 4.7% in 9 controls (p less than 0.025). Similar results were obtained when 6-nitrobenzylthioinosine, which inhibits adenosine efflux from hypoxic cells, was added to the perfusion (n = 5, p less than 0.025). The addition of the adenosine analogue R(-)-phenylisopropyladenosine [R(-)-PIA] conferred protection, so that now only 12.5 +/- 2.5% of deep mTAL cells exhibited severe morphological damage (n = 7, p less than 0.005). The protective effect of R(-)-PIA was minimized by 8-phenyltheophylline, which blocks adenosine receptors. The S(+)-isomer of PIA was significantly less potent than R(-)-PIA in protecting against hypoxic injury. These results suggest that endogenous adenosine may play a role in modifying the injurious effects of anoxia on medullary cells, by inhibiting active transport.
Insights
Adenosine protects kidney cells from damage caused by low oxygen. Blocking adenosine worsened injury, while adding a specific adenosine analogue protected medullary thick ascending limb cells.
Area of Science:
- Nephrology
- Cellular Biology
- Biochemistry
Background:
- The medullary thick ascending limb (mTAL) in rat kidneys is susceptible to hypoxic injury due to its environment and active transport demands.
- Endogenous transport inhibitors could potentially mitigate this cellular damage.
Purpose of the Study:
- To investigate the role of adenosine in protecting mTAL cells against hypoxic injury in isolated perfused rat kidneys.
- To determine if adenosine modulates active transport to confer protection.
Main Methods:
- Isolated rat kidneys were perfused for 60 minutes.
- Adenosine deaminase was added to assess injury exacerbation.
- 6-nitrobenzylthioinosine was used to inhibit adenosine efflux.
- Adenosine analogues, R(-)-phenylisopropyladenosine [R(-)-PIA] and its S(+)-isomer, were administered.
- 8-phenyltheophylline was used to block adenosine receptors.
Main Results:
- Adenosine deaminase significantly exacerbated mTAL cell damage (89.4% vs 74.9% in controls).
- Inhibition of adenosine efflux also worsened injury.
- R(-)-PIA conferred significant protection, reducing severe damage to 12.5% of cells.
- The protective effect of R(-)-PIA was diminished by 8-phenyltheophylline, and the S(+)-isomer was less potent.
Conclusions:
- Endogenous adenosine plays a protective role against anoxic injury in medullary cells.
- Adenosine likely exerts its protective effects by inhibiting active transport in the mTAL.
- Adenosine receptor activation is crucial for this protective mechanism.