Cell Plasticity in the Kidney Collecting Duct of Hsd11b2 KO Mice and Rats
Authors: Ward Mairi , Assmus Adrienne M. , Mullins Linda J. , Peter Audrey , Mansley Morag K. , Bradley Mark , Mullins John 
Published: April 2020

The cortical collecting duct (CCD) of the kidney is responsible for approximately 4–5% of total sodium and 10% of total water reabsorption and is lined by two functionally distinct cell types, principal cells (PC) and intercalated cells (IC) α and β. However, a degree of plasticity has been reported in these cells in mature kidneys
1, as well as the presence of intermediate/mixed cells expressing both PC and IC markers
2.

In this study, we investigate whether cell plasticity plays a role in diseased kidney collecting duct, specifically the syndrome of apparent mineralocorticoid excess (SAME) driven by mutation of the Hsd11b2gene. In humans, SAME contributes to a high neonatal and infant mortality rate, with those patients surviving into adulthood developing hypertension, sodium retention and hypokalemia. Despite extensive research into the metabolic, vascular and renal consequences of the Hsd11b2gene knock‐out (KO) in both mice and rats, the effect of the KO on CCD epithelial plasticity has not been previously reported. The Hsd11b2gene is expressed in principal cells and it was hypothesized that loss of its expression may result in changes in the ratio of PC and IC cells within the CCD.

PCs and ICs in the CCD were counted in WT and KO mice and rats following immunofluorescent staining for PC‐ and IC‐specific markers in paraffin‐embedded kidney sections. Images were analyzed using ImageJ software and the data analyzed using GraphPad Prism. All data are expressed as mean ± SEM of the mean. Significance was assessed using Tukey’s multiple comparisons test with p<0.0001.

At 4 weeks KO mouse kidneys displayed a significant reduction in the proportion of PCs per CD compared to controls (52.1 ± 1.9 % vs. 73.0 ± 1.9 %) and this remained the case at 17 weeks of age (54.1 ± 1.8 % vs. 72.2 ± 1.3 %). No significant change in the proportion of IC cells was observed between any of the groups studied. A significant increase in intermediate/ mixed cells was observed between WT and KO at 4 weeks (8.4 ± 1.2 % vs.25.9 ± 2.0 %) and at 17 weeks (6.5 ± 0.8 % vs. 22.1 ± 2.0 %). These findings were mirrored in the rat KO with a significant reduction in the proportion of PCs compared to controls at both 5 weeks (60.69 ± 2.51 % vs. 73.30 ± 1.84 %) and 24 weeks (38.40 ± 2.07 % vs. 66.80 ± 1.94 %). The concomitant decrease in PC proportion and increase in intermediate/mixed cell proportion observed may indicate that PCs are dedifferentiating to a mixed cell type which is in line with previous reports of a cell expressing both PC and IC markers predominating under physiological stress or genetic manipulation.
1

These results, showing plasticity consistent across mice and rat models of SAME, will be particularly important if they can be shown to have clinical relevance in humans in either physiological or pathophysiological conditions. If these findings are mirrored in humans, this would provide greater insight into the dynamic plasticity observed in disease in the mature kidney.

Support or Funding Information

This work was funded by the EPSRC/MRC Optima CDT, Kidney Research UK and the BHF