Functional impairment of renal organic cation transport in experimental diabetes.
This study was designed to determine the effect of diabetes on the function of the renal organic cation transport system that mediates the excretion of a wide variety of toxicants and drugs. The experiments compared the ability of renal cortex slices from streptozotocin-induced diabetic and non-diabetic rats to accumulate the model cation, 14C-tetraethylammonium under controlled conditions. Initial experiments demonstrated a progressive decline in tetraethylammonium accumulation with increasing duration of diabetes. The maximal decrease was observed at 21 days after streptozotocin injection. Time-dependent incubations revealed that tetraethylammonium uptake from both diabetic and non-diabetic rats followed a curvilinear pattern expected of an active process. However, at steady state the diabetic-derived slices accumulated a significant 38% less tetraethylammonium versus slices from non-diabetics. Concentration-dependent incubations of tetraethylammonium (0.01-10 mM, 60 min.) demonstrated saturable transport in both diabetic and non-diabetic slices with a significantly decreased capacity of diabetic-derived slices to accumulate tetraethylammonium. Cellular respiration rates in the two groups were not different. Insulin treatment of the diabetic rats prevented the transport decline. While the causative factor of the transport impairment in diabetes is unresolved, this study documents an aspect of diabetic nephropathy that has not been previously reported but which may have important implications for renal excretion of cationic drugs and toxicants. The results also provide a mechanism for the well-documented "protection phenomenon" by which the kidneys of diabetic rats are resistant to nephrotoxicity induced by the chemotherapeutic agent cisplatin.
Grover
Brett
B
Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati Medical Center, Cincinnati, OH 45267-0004, USA.
Auberger
Christopher
C
Sarangarajan
Rangaprasad
R
Cacini
William
W
D000818:Animals; D001692:Biological Transport; D001786:Blood Glucose / Q000032:analysis; D002250:Carbon Radioisotopes; D002412:Cations / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007328:Insulin / Q000627:therapeutic use; D007672:Kidney Cortex / Q000378:metabolism*; D008297:Male; D011190:Potassium Cyanide / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019789:Tetraethylammonium / Q000378:metabolism; D013997:Time Factors
D001786:Blood Glucose; D002250:Carbon Radioisotopes; D002412:Cations; D007328:Insulin; D019789:Tetraethylammonium; D011803:Quinine; D011190:Potassium Cyanide