Functional Impairment of Renal Organic Cation Transport in Experimental Diabetes

Abstract

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, 14 C-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 nondiabetic 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.

Reduced Expression of Organic Cation Transporters rOCT1 and rOCT2 in Experimental Diabetes

“…The decline was rapid with rOCT2 expression decreased by more than 50% within 7 days after induction of diabetes and that for rOCT1 by 14 days. These results coincide with the functional decline pattern for TEA uptake in cortex slices derived from STZ diabetic rat kidneys that were recently reported by Grover et al (2002). In this study, decreased TEA accumulation in rat renal cortex slices was evident after 7 days of STZ-induced diabetes and was attenuated by 14 days with the maximal decline detected by 21 days.…”

“…The glycation process can be reasonably fast. We have documented a near doubling of glycation of hemoglobin within 7 days after STZ injection in rats (Grover et al, 2002). Although rOCT1 …”

“…Our laboratory has demonstrated a progressive impairment of the ability of the model organic cation tetraethylammonium to accumulate in freshly isolated proximal tubular cells (Rathi and Cacini, 1996) and renal slices prepared from streptozotocin (STZ)-induced diabetic rats (Grover et al, 2002). The renal organic cation transport system of the proximal tubule plays an important role in mediating the removal of a variety of toxicants and drugs from the body (for reviews, see Pritchard and Miller, 1996;Inui et al, 2000).…”

Organic cation transporters

“…Long-term regulation is evidenced by expression of cation transport in rat kidney that is gender dependent and changed during diabetes (Bowman and Hook 1972;Grover et al 2002). In male rats, basolateral uptake of TEA into renal proximal tubule cells was twice as high as in female rats and correlated with increased levels of rOCT2 mRNA and protein .…”

Diabetes and hypertriglyceridemia modify the mode of acetaminophen-induced hepatotoxicity and nephrotoxicity in rats and mice

“…1 reported in diabetes such as polyuria, glucosuria, and glomerular hypertrophy (Sharma et al, 1999). These conExperimental diabetes has been shown to protect against the nephrotoxic effects of several compounds including cyclosporine A, gentamicin, cisplatin, mercuric chloride and cephaloridine (Vaamonde et al, 1984;Elliott et al, 1985;Valentovic et al, 1991;Cacini et al, 1993;Grover et al, 2002;Saad and Naijar, 2005). Challenge with nephrotoxicants is known to stimulate a compensatory tissue repair response in the kidney (Dobyan et al, 1980;Haagsma and Pound, 1980;Laurent et al, 1988;Korrapati et al, 2005), suggesting that such repair mechanisms underlie this diabetes-induced protection.…”