Spontaneous One-Kidney Rats are More Susceptible to Develop Hypertension by DOCA-NaCl and Subsequent Kidney Injury Compared to Uninephrectomized Rats

22 There is little clinical data of how hypertension may influence individuals with nephron 23 deficiency in the context of being born with a single kidney. We recently developed a new rat 24 model (the HSRA rat) that is born with a single kidney and exhibits progressive kidney injury 25 and decline in kidney function with age. We hypothesized that deoxycorticosterone acetate 26 (DOCA)-salt would induce a greater increase in blood pressure and therefore accelerate 27 progression of kidney injury in rats born with a solitary kidney compared to rats that have 28 undergone unilateral nephrectomy. Time course evaluation of blood pressure, kidney injury, and 29 renal hemodynamics was performed in 6 groups of animals from week 13 -18: (1-2) DOCA+S or 30 Placebo+S (solitary kidney); (3-4) DOCA+C or Placebo+C (two-kidney control); and (5-6) 31 DOCA+UNX8 or Placebo+UNX8 (two-kidney control that have undergone uninephrectomy). 32 DOCA+S treated rats demonstrated a significant rise (p<0.05) in blood pressure (192±4 mmHg), 33 proteinuria (205±31 mg/24hr) and decline in GFR (600+42 μl/min/gKW) relative to 34 DOCA+UNX8 (173±3 mmHg, 76±26 mg/24hr, 963+36 μl/min/gKW) and DOCA+C (154±2 35 mmHg, 7±1 mg/24hr, 1484+121 μl/min/gKW). Placebo groups showed no significant change 36 among the three groups. An assessment of renal injury markers via real-time PCR/western 37 analysis and histological analysis was concordant with the measured physiological parameters. In 38 summary, congenital solitary kidney rats are highly susceptible to the induction of hypertension 39 compared to uninephrectomized rats, suggesting that low nephron endowment is an important 40 driver of elevated blood pressure, hastening nephron injury through transmission of elevated 41 systemic blood pressure, and thereby accelerating decline in kidney function. 42