Investigating the Interaction of Nephron Deficiency and Diabetes using a Novel One‐Kidney Rat Model
Authors: Cobb Meredith , Wu Wenjie , Johnson Ashley , Garrett Michael R. 
Published: June 2021

According to the Centers for Disease Control, 1 in 3 adults with diabetes may have chronic kidney disease (CKD). CKD is also believed to have an association with low nephron number, with studies indicating that individuals believed to be nephron deficient are more likely to develop renal disease. Unfortunately, studying the impact of nephron number on disease outcome in humans is difficult due to the variation of nephrons from individual to individual, thus animal models are ideal for such investigations. Many investigators utilize unilateral nephrectomy in rodent models to study the loss of nephrons on susceptibility to develop cardiovascular and metabolic dysfunction. In contrast, our lab has developed a unique model of nephron deficiency via spontaneous unilateral renal agenesis. The HSRA model (Heterogeneous Stock model of unilateral Renal Agenesis) gives rise to 50–75% of offspring that are born with a single kidney (HSRA‐S) while the remaining pups are born with two kidneys (HSRA‐C). The model provides the unique advantage of directly comparing congenital one‐kidney, nephron‐deficient animals (HSRA‐S, ~20,400 nephrons) with uni‐nephrectomized two‐kidney animals (HSRA‐UNX, ~25,100 nephrons) and two‐kidney control animals (HSRA‐C, ~50,000 nephrons) in the same model. Previous work has shown that HSRA‐S rats develop increased blood pressure and renal dysfunction with age compared to HSRA‐UNX and HSRA‐C littermates.

Our central hypothesis is that a secondary stressor of hyperglycemia (Type 1 diabetes) will cause more severe decline in renal function in the HSRA‐S rat compared to HSRA‐UNX, despite the small difference in nephrons, followed by HSRA‐C. There are two studies currently underway. (1) Investigation of age‐related differences in glucose handling and insulin resistance, along with renal and cardiovascular parameters, between the HSRA‐S and HSRA‐C (n=8 per group per sex) from 5 months to 20 months of age in both males and females. Preliminary data indicates a potential difference in early glucose tolerance between male and female HSRA rats at week 25 (Figure 1), with no significant difference in renal injury (proteinuria); (2) Investigation of the impact of elevated hyperglycemia (induced by streptozotocin) on cardiovascular and renal parameters in the STZ+HSRA‐S, STZ+HSRA‐C, STZ+HSRA‐UNX (n=6–8 per group) versus controls for all three groups (n=6–8 each group). This study has just initiated.

We expect to observe impaired renal function and more severe renal pathology in the HSRA‐S animals versus the HSRA‐UNX followed by HSRA‐C, providing evidence of an association between lower nephron number and development of renal disease secondary to hyperglycemia. Establishing nephron deficiency as a risk factor for hyperglycemia‐associated renal pathology is an essential step in the management of diabetic patients, and we hope to contribute to the growing knowledge of the relationship between nephron number and disease.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.