Abstract Body: Background: Short-term kidney injury caused by unilateral ureteral obstruction (UUO) has been shown to result in long-term complications, including hypertension and chronic kidney disease. Nevertheless, it remains unclear whether congenital renal hypoplasia and a reduced nephron number exacerbate these long-term effects.
Methods: Male and female mice with renal hypoplasia (ROP Os/+; n=5 male/n=5 female) and wild-type controls (ROP +/+; n=5 male/n=5 female) underwent either unilateral ureteral obstruction (UUO) or sham surgery, followed by ureteral clip removal on day 7 to model reversible UUO (RUUO). Blood pressure and heart rate were monitored weekly via telemetry for 5 weeks. Renal artery resistive index (RI) was assessed by ultrasound. At the study endpoint, urine was collected to measure cystatin C (CysC) and neutrophil gelatinase-associated lipocalin (NGAL). Kidney tissues were collected for histological analysis and gene expression profiling.
Results: At baseline, mean arterial pressure (MAP) and heart rate (HR) were similar between ROP +/+ and ROP Os/+ mice across both sexes. Following RUUO, MAP was significantly elevated, and HR decreased in ROP Os/+ and ROP +/+ mice compared to sham controls. Notably, ROP Os/+ mice showed a 25–30 mmHg higher MAP and a 100–150 beats/min lower HR than ROP +/+ mice by 5 weeks post-clip removal. Renal artery resistive index (RI) was increased in both RUUO groups compared to sham mice, with ROP Os/+ mice exhibiting a greater increase, indicating reduced renal blood flow.
Urinary levels of CysC and NGAL were approximately two-fold higher in RUUO ROP Os/+ mice than in ROP +/+ mice. Histologically, ROP Os/+ mice displayed greater tubular cast formation and increased fibrosis and α-SMA levels (3-fold vs. 2-fold in ROP +/+). Fibrosis-related gene expression was significantly upregulated in ROP Os/+ mice, as shown by pathway analysis and confirmed by RT-PCR for Fn1, collagen I, and vimentin. Additionally, Mac2+ inflammatory cell infiltration was more pronounced in ROP Os/+ mice. No significant sex differences were observed for measured parameters.
Conclusion: These findings indicate that mice with renal hypoplasia and reduced nephron endowment (ROP Os/+) exhibit significantly greater hypertension, renal inflammation, and kidney injury than wild-type mice (ROP +/+) following reversible ureter obstruction. The results highlight the heightened vulnerability of hypoplastic kidneys to long-term damage after transient injury.