Abstract P1124: Nephron Deficiency and Hyperglycemic Renal Injury Using a Novel One Kidney Rat Model

Abstract

Patients with hypertension or diabetes are at higher risk for developing chronic kidney disease (CKD). Low nephron number has been linked with susceptibility to develop hypertension and CKD, but a clear connection between nephron number and hyperglycemic renal injury has not been established. Thus, we seek to investigate the association between nephron deficiency and the development of diabetic kidney disease using a unique model of nephron deficiency, the HSRA rat. Offspring of HSRA are born with a single kidney 50-75% of the time with the remaining pups born with two kidneys. This provides the advantage of being able to directly compare congenital one-kidney, nephron-deficient rats (HSRA-S, ~20,400 nephrons) with nephrectomized two-kidney rats (HSRA-UNX, ~25,100 nephrons) and two-kidney control rats (HSRA-C, ~50,000 nephrons). Previous work has shown that HSRA-S develops increased renal dysfunction with age compared to HSRA-UNX and HSRA-C, which is greatly exacerbated in the presence of DOCA hypertension. Our hypothesis is that a secondary stressor of hyperglycemia in the context of low nephron number will similarly cause greater decline in renal function in HSRA-S compared to HSRA-UNX and HSRA-C. Streptozotocin (STZ) was administered at 9 weeks of age in all three groups and animals were followed until week 24. Despite overt hyperglycemia (350-450 mg/dl), diabetic groups did not develop increased proteinuria compared to their non-diabetic counterparts. Notably, a significant increase in kidney weight was observed in HSRA-S+STZ compared to HSRA-S (kidney weight to body weight ratio [mg/g] 4.8 ± 0.3089 for HSRA-S vs 7.8 ± 1.204 for HSRA-S+STZ, p=0.02), suggesting that hyperglycemia has a deleterious impact on kidney function via hyperfiltration and hypertrophy. Despite no significant effect on proteinuria after an “early insult,” we are investigating the impact of hyperglycemia after overt injury (“late insult”) is observed in HSRA-S (week >24). We will also revisit an “early insult” of hyperglycemia with the addition of modest hypertension (130 mmHg) via DOCA, which represents patients with both diabetes and hypertension . Through this research, we hope to contribute to the growing knowledge of the relationship between nephron number and disease.