Abstract 082: On the Significance of Urinary Renin in Diabetic Kidney Disease: A Critical Role of Impaired Proximal Tubular Reabsorption

Abstract

Increased expression of renin in the kidney collecting tubule of rodents made diabetic by streptozotocin (STZ) has been well demonstrated but whether this site is the main source of urinary renin is unknown. We wanted to examine the origin and significance of urinary renin in diabetic kidney disease (DKD). Total and active renin was evaluated in urines from people with longstanding type 1 diabetes of more than 25 years, with (n=36) or without DKD (n=38) (eGFR 101 vs. 39 mL/min/1.73m 2 ; p<0.001). Mice given STZ (n=15) or vehicle (n=8) 20 weeks prior to study were also studied. In people with DKD, total renin was markedly increased compared to people without DKD (82 vs. 49 pg/mg Cr; p=0.023). Active renin was also significantly increased in people with DKD compared to people without DKD (3.2 vs. 1.3 pg/mg Cr; p<0.001). In mice with STZ-induced DKD a significant increase in renin was found compared to controls (1093±319 vs. 64±18 pg/mg Cr; p=0.0001). To examine the role of filtration and tubular reabsorption on urinary renin, human active renin was measured in urines from non-diabetic mice infused with human recombinant renin (hrRenin) (n=8), a combination of lysine and hrRenin (n=5) and non-infused controls (n=15). Urines of mice infused with a combination of lysine (a blocker of proximal tubular protein reabsorption) and hrRenin had markedly higher urinary human active renin than those of controls (179±129 vs. 1.6±0.4 pg/mg Cr; p=0.001). The values were also markedly higher than those of mice infused with hrRenin only (4.4±1.1 pg/mg Cr; p=0.003). The effect of lysine was also evaluated in regard to endogenous mouse renin. Urinary mouse renin in mice infused with lysine (n=5) was markedly increased compared to non-infused controls (n=18) (22360±8673 vs. 346±82 pg/mg Cr; p=0.001). In conclusion, in humans with DKD, urine concentrations of both total and active renin are increased. In mice with STZ-induced DKD, urine total renin is also markedly increased. The data further demonstrate that 1) renin is both filterable and reabsorbable in normal mice and 2) the increase of urinary renin in DKD can be attributed largely to impaired reabsorption mainly in the proximal tubule.