Cells of renin lineage are adult pluripotent progenitors in experimental glomerular disease

Abstract

Modified vascular smooth muscle cells of the kidney afferent arterioles have recently been shown to serve as progenitors for glomerular epithelial cells in response to glomerular injury. To determine whether such cells of renin lineage (CoRL) serve as progenitors for other cells in kidney disease characterized by both glomerular and tubulointerstitial injury, permanent genetic cell fate mapping of adult CoRL using Ren1cCreER × Rs-tdTomato-R reporter mice was performed. TdTomato-labeled CoRL were almost completely restricted to the juxtaglomerular compartment in healthy kidneys. Following 2 wk of antibody-mediated focal segmental glomerulosclerosis (FSGS) or 16 wk of ⅚ nephrectomy-induced chronic kidney diseases, tdTomato-mapped CoRL were identified in both interstitial and glomerular compartments. In the interstitium, PDGFβ receptor (R)-expressing cells significantly increased, and a portion of these expressed tdTomato. This was accompanied by a decrease in native pericyte number, but an increase in the number of tdTomato cells that coexpressed the pericyte markers PDGFβ-R and NG2. These cells surrounded vessels and coexpressed the pericyte markers CD73 and CD146, but not the endothelial marker ERG. Within glomeruli of reporter mice with the ⅚ nephrectomy model, a subset of labeled CoRL migrated to the glomerular tuft and coexpressed podocin and synaptopodin. By contrast, labeled CoRL were not detected in glomerular or interstitial compartments following uninephrectomy. These observations indicate that in addition to supplying new adult podocytes to glomeruli, CoRL have the capacity to become new adult pericytes in the setting of interstitial disease. We conclude that CoRL have the potential to function as progenitors for multiple adult cell types in kidney disease.

Tracking the stochastic fate of cells of the renin lineage after podocyte depletion using multicolor reporters and intravital imaging

“…These results are consistent with the previously established distribution of CoRL, which includes the glomerular afferent arterioles, mesangium, the parietal layer of Bowman’s capsule as well as various tubule segments and interstitium [10, 11, 19, 20]. Also, the relatively low number of CoRL observed in the present study in the glomerular tuft after podocyte injury is in good agreement with our previous work [13, 31]. …”

Activated ERK1/2 increases CD44 in glomerular parietal epithelial cells leading to matrix expansion

“…Indirect immunoperoxidase and immunofluorescence staining were performed on 4μm tissue sections from frozen (Sheep IgG, CD44 variant 3, 7 & 10, hyaluronic acid binding protein and leukocytes staining) or formalin fixed paraffin embedded (all other) renal biopsies as described previously 21, 24, 53–55 In brief, optimum cutting temperature compound was removed from frozen sections by washing in PBS followed by post fixation in −20°C methanol and a subsequent wash in PBS. Paraffin was removed from formalin-fixed sections using Histoclear (National Diagnostics, Atlanta, GA, USA) and rehydrated in a graded series of ethanol.…”

Can podocytes be regenerated in adults?

“…First, a 5/6 nephrectomy remnant kidney model was induced surgically in CoRL reporter mice [79]. As expected, mice developed mild FSGS [79]. However, in a subpopulation of glomeruli that did not have obvious segmental scarring, labeled CoRL could be detected, and a subset of these cells co-expressed several podocyte proteins (FIGURE 2) [79].…”

“…First, a 5/6 nephrectomy remnant kidney model was induced surgically in CoRL reporter mice [79]. As expected, mice developed mild FSGS [79].…”