Kidney Week

Abstract: FR-PO061

Low Nephron Endowment-Induced Compensatory Nephron Hypertrophy Causes ER Stress Making the Nephrons More Susceptible to Injury

Session Information

• AKI: Tubules, Metabolism, New Models
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Zhang, Hongxia, Augusta University, Augusta, Georgia, United States

Hongxia Zhang,

• Xu, Jinxian, Augusta University, Augusta, Georgia, United States

Jinxian Xu,

• Dai, Caihong, Augusta University, Augusta, Georgia, United States

Caihong Dai,

• Lv, Shijun, Weifang Mecial College, Weifang, Shandong, China

Shijun Lv,

• Chen, Jian-Kang, Augusta University, Augusta, Georgia, United States

Jian-Kang Chen,

Background

Functioning nephrons respond to nephron deficits by increases in size and mass but not in number. Such a growth response is called compensatory nephron hypertrophy (CNH), which can occur in many situations. However, the pathogenic role of CNH in determining the susceptibility and severity of AKI and the underlying molecular mechanisms remain poorly understood.

Methods

We generated an mVPS34 gene-floxed mouse and crossed it with a HoxB7.Cre mouse. Utilizing a long-term selective breeding strategy for a low HoxB7.Cre activity, we established a stable sub-strain of renal collecting system-specific mVPS34 knockout (KO) mice with a genotype of mVPS34^flox/flox;HoxB7.Cre⁽⁺⁾. These KO mice were challenged with bilateral renal ischemia/reperfusion (I/R) insults at 8 weeks of age. Gender-matched littermates with a genotype of mVPS34^flox/flox;HoxB7.Cre^(-) were used as controls (Ctrl).

Results

The KO mice appear healthy, with normal levels of BUN, serum creatinine, and blood pressure (measured by telemetry). Using the newly developed accurate glomerular counting method, we found that KO mice have a 60% congenital nephron deficit, compared to Ctrl littermates: 11066 ± 776.5 (N=8 mice) vs. 27915 ± 1293 (N=11 mice) nephrons/mouse, with both left and right kidneys containing similarly lower nephron numbers. The mean renal glomerular and tubular areas of KO mice were significantly larger, with a 38% increase in single nephron GFR, confirming congenital nephron deficit-induced CNH. A 15-minute ischemia followed by 24 hours of reperfusion caused markedly more severe ischemia-reperfusion injury (IRI) and significant increases in both serum creatinine (Scr) and BUN in KO mice while Ctrl mice exhibited minimal structural damage but had no increase in either Scr or BUN. A 30-minute I/R also caused IRI in both KO mice and Ctrl mice, with significantly more severe morphological and functional damage in KO mice than in Ctrl mice. Mechanistic studies revealed markedly higher levels of Bip and C/EBP homologous protein (CHOP) in the KO mice, indicating the elevation of ER stress.

Conclusion

The congenital CNH caused by mVPS34 deletion in collecting duct is more susceptible and severe to ischemic nephron injury, which is likely mediated by elevated ER stress.

Funding

• NIDDK Support