Abstract: PO0431
Renal Papillary Function and Repair After Reversible Ureteral Obstruction
Session Information
- AKI: Repair and Progression
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- de Caestecker, Mark P., Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Delgado, Rachel, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Brewer, Maya, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Yang, Min, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Yang, Haichun, Vanderbilt University Medical Center, Nashville, Tennessee, United States
Background
Models of reversible UUO (R-UUO) have provided insight into the mechanisms of repair in the renal cortex, but little is known about the mechanisms or extent of renal papillary repair after reversal of obstruction. Here we characterize long-term functional and structural papillary repair in a new mouse model of R-UUO.
Methods
Vascular clamps are placed on the L ureter, removed on day 7, and a R nephrectomy (Nx) performed on day 17. We evaluated serial BUN; transdermal GFR (tGFR); urinary osmolarity (OSM) after water restriction; histology and fibrosis; tubules, interstitium, and capillaries by IF with segment-specific markers, markers of repair, and lineage analysis with Six2-CRE; R26R-td Tomato reporter mice to assess repair of nephronic epithelium.
Results
At clamp removal (day 0) all mice had hydronephrosis. 60-80% survived 48hrs after Nx, and day 14 BUN in Nx vs. R-UUO+Nx was 18.5 (0.9) vs. 42.6 (8.5) mg/dl, p<0.001, indicating reversal and consistent injury. tGFR was reduced at day 28 (991.0 (46.6) vs. 569.8 (82.6) ml/min/100gm, p<0.001), reversed by day 84, with decreased urinary OSM up to day 84 (3525 (106.9) vs. 1718 (175.7) mOsm/L, p<0.0001). There was cortical fibrosis from 0-84 days. Fibrosis increased day 0>28 in the papilla but was absent by day 84. There was papillary necrosis days 0-3; repopulation of tubular structures starting day 7 with disorganized tubulointerstitial repair by day 28 but normal histology by day 84. There was loss of AQP1 (descending thin limb, DTL) and AQP2 but not LTL staining (distal collecting duct, CD) days 3>28. AQP1 and 2 were restored by day 84, but there was a reduction in capillary density by CD31 staining days 14>84. Lineage analysis showed persistent Six2 lineage in the papilla at day 28, indicating effective repair of AQP1- DTL. There was a marked increase in Ki67+ Six2 lineage and LTL+ CD cells days 3-7 after reversal, but no expression of the de-differentiation marker, Sox9, in the papilla.
Conclusion
There is robust, Sox9-independent repair of tubules in the papilla that is initially disorganized but ultimately restores tubular organization after R-UUO. Despite this, a persistent defect in urinary concentrating capacity associated with decreased papillary capillary density, suggests that despite robust tubular repair, disorganized vascular integrity results in long-term papillary dysfunction after R-UUO.
Funding
- NIDDK Support