Nephron-deficient HSRA rats exhibit renal injury with age but have limited renal damage from streptozotocin-induced hyperglycemia

Abstract

Hypertension and diabetes are the greatest factors influencing the progression of chronic kidney disease (CKD). Investigation into the role of nephron number in CKD alone or with hypertension has revealed a strong inverse relationship between the two; however, not much is known about the connection between nephron number and diabetic kidney disease. The HSRA rat, a novel model of nephron deficiency, provides a unique opportunity to study the association between nephron number and hypertension and diabetes on CKD. HSRA rats exhibit failure of one kidney to develop in 50-75% of offspring while remaining offspring are born with two kidneys. Rats born with one kidney (HSRA-S) develop significant renal injury with age compared to two-kidney littermates (HSRA-C). Induction of hypertension as a secondary stressor leads to significantly more renal injury in HSRA-S compared to HSRA-C and HSRA-UNX (nephrectomized HSRA-C rats). The current study sought to address the hypothesis that nephron deficiency in the HSRA rat would hasten renal injury in the presence of a secondary stressor of hyperglycemia. HSRA animals did not exhibit diabetes-related traits at any age, thus streptozotocin (STZ) was used to induce hyperglycemia in HSRA-S, HSRA-C, and HSRA-UNX. STZ and vehicle-treated animals were followed for 15 weeks. STZ animals developed robust hyperglycemia, but in contrast to the response to hypertension, HSRA-S nor HSRA-UNX animals developed proteinuria compared to vehicle. In total, our data indicates that hyperglycemia from STZ alone does not have a significant impact on the onset or progression of injury in young one kidney HSRA animals.