Amphotericin B Decreases Adenylyl Cyclase Activity and Aquaporin-2 Expression in Rat Kidney

Title: Amphotericin B Decreases Adenylyl Cyclase Activity and Aquaporin-2 Expression in Rat Kidney
Authors: Kim, Soo Wan; Yeum, Chung Ho; Kim, Sunmi; Oh, YoonWha; Choi, Ki Chul; Lee, Jongun
Publisher: Journal of Laboratory and Clinical Medicine
Date Published: October 01, 2001
Reference Number: 556
The present study was intended to examine whether the amphotericin-induced urinary concentration defect can be related to an altered regulation of aquaporin (AQP) water channels in the kidney. Male Sprague-Dawley rats were injected with amphotericin B (6 mg/kg/d, IP ) for 21 days. The protein expression of AQP1-3, Gsa, and adenylyl cyclase was determined in the kidney. To further specify the primary point of dysregulation of AQP channels that are activated by the arginine vasopressin/cyclic adenosine monophosphate (AVP/cAMP) pathway, different components of adenylyl cyclase complex were separately examined for their cAMP-generating activities. Amphotericin treatment resulted in kidney failure associated with decreased tubular water reabsorption and increased urinary flow rate. The expression of AQP2 proteins was significantly decreased in the outer medulla and inner medulla but not in the cortex. The expression of AQP2 proteins in the membrane fraction changed in parallel with that in the cytoplasmic fraction, suggesting a preserved targeting. Neither the expression of AQP1 nor that of AQP3 was significantly affected in the cortex, outer medulla, or inner medulla. The cAMP generation in response to AVP or sodium fluoride was decreased, whereas that to forskolin was not significantly altered. The expression of Gsa proteins was decreased in the inner medulla, whereas that of adenylyl cyclase VI remained unaltered. These findings indicate that the amphotericin-induced urinary concentration defect may in part be causally related to a reduced abundance of AQP2 channels in the kidney. It is also suggested that the primary impairment in the pathway leading to the activation of AQP channels that are regulated by the AVP/cAMP pathway lies at the level of G proteins.

This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

The drug amphotericin-B can injure the kidney, causing it to be unable to concentrate urine. This inability results in the patient voiding unusually large volumes of urine. Kim, et al., tested to see whether amphotericin-B caused this defect by reducing the number of Aquaporin-2 (AQP2) in the principal cells of the kidney collecting duct. AQP2 helps the kidney concentrate urine by allowing water to flow into the collecting duct cells.

The researchers injected rats with amphotericin B over a three-week period. As expected, kidney failure occurred. The researchers then examined the kidneys to determine the number of AQP2s (as well as AQP1, AQP3 and Gsa proteins and adenylyl cyclase — other components involved in urine concentration). They found that though the numbers of AQP1 and AQP3 were not significantly affected, the numbers of AQP2 dropped significantly both in the membrane and interior of the collecting duct cells. The number of Gsa protein was decreased, whereas that of adenylyl cyclase were unaltered.

The researchers’ findings suggest that the inability to concentrate urine caused by amphotericin-B may be related to a reduction in the number of AQP2s in the kidney. They also suggest that the G protein may be the site that is primarily injured by amphotericin-B, as indicated by the reduction of Gsa proteins.