Intact renal afferent arteriolar autoregulatory responsiveness and enhanced AngII sensitivity in diabetic mice

Abstract

The db/db mouse is a genetic model of type II diabetes that exhibits progressive diabetic renal disease. To test the hypothesis that reduced afferent arteriolar (AA) responsiveness to increases in renal perfusion pressure and enhanced AngII sensitivity lead to impaired renal function in diabetes, experiments were conducted using the mouse in vitro juxtamedullary nephron technique utilizing euglycemic (NG) and hyperglycemic (HG; 5 vs 30mM glucose) blood perfusion and superfusion conditions. Kidneys were harvested from male db/db (53±1g;n=23; p<0.05) and lean (31±1g;n=23) littermates (db/m) at 18 wks and perfused with blood from donor rats. Blood glucose levels were elevated in db/db compared to lean mice (530±13, n=13 vs 141±14mg%, n=14). Baseline AA diameters (95mmHg) of db/db (14.3±0.6μm; n=26) were not different from lean (12.8±0.5μm; n=24). Renal perfusion pressure was increased from 75–155mmHg at 20mmHg steps. Responses of AA of db/db-HG were not different from lean-NG (−15±3 vs −9±5%; 95–155mmHg). Acute incubation (3hr) of db/db kidneys in NG caused a significant attenuation of the response to pressure (−1±2%). Incubation of lean kidneys in HG tended to augment the response to pressure (−18±4%; p=0.07). Significant vasoconstriction to 10nM AngII was observed in all groups (−18±4% db/db-HG, n=11; −20±5% lean-NG, n=12; −17±4% db/db-NG, n=15; −21±3% lean-HG, n=9). However, 1nM AngII produced a significant constriction only in AA of db/db-HG (−12±4%). In summary, enhanced sensitivity to AngII is observed in AA of db/db kidneys, while AA responses to increases in renal perfusion pressure are intact. Enhanced sensitivity to AngII maybe linked to reduced renal function in this diabetic model. NIDDK-62003 & P20RR018766