Cells of Renin Lineage Are Progenitors of Podocytes and Parietal Epithelial Cells in Experimental Glomerular Disease

Abstract

Glomerular injury leads to podocyte loss, a process directly underlying progressive glomerular scarring and decline of kidney function. The inherent repair process is limited by the inability of podocytes to regenerate. Cells of renin lineage residing alongside glomerular capillaries are reported to have progenitor capacity. We investigated whether cells of renin lineage can repopulate the glomerulus after podocyte injury and serve as glomerular epithelial cell progenitors. Kidney cells expressing renin were genetically fate-mapped in adult Ren1cCreER×Rs-tdTomato-R, Ren1cCre×Rs-ZsGreen-R, and Ren1dCre×Z/EG reporter mice. Podocyte depletion was induced in all three cell-specific reporter mice by cytotoxic anti-podocyte antibodies. After a decrease in podocyte number, a significant increase in the number of labeled cells of renin lineage was observed in glomeruli in a focal distribution along Bowman's capsule, within the glomerular tuft, or in both locations. A subset of cells lining Bowman's capsule activated expression of the glomerular parietal epithelial cell markers paired box protein PAX2 and claudin-1. A subset of labeled cells within the glomerular tuft expressed the podocyte markers Wilms tumor protein 1, nephrin, podocin, and synaptopodin. Neither renin mRNA nor renin protein was detected de novo in diseased glomeruli. These findings provide initial evidence that cells of renin lineage may enhance glomerular regeneration by serving as progenitors for glomerular epithelial cells in glomerular disease characterized by podocyte depletion.

Podocyte Number in Children and Adults

“…53,54 Podocytes can be induced to proliferate in vitro when cultured from freshly isolated glomeruli, 55 but these cells express low levels of many of the podocyte-specific differentiation markers, suggesting that podocytes are only capable of proliferating after they have dedifferentiated to a certain degree. Recent evidence suggests that progenitor cells residing in the JGA 56 and Bowman's capsule (PECs) [57][58][59][60][61] may give rise to podocytes. Other lines of evidence suggest that new podocytes may arise from bone marrow.…”

Intravital imaging of podocyte calcium in glomerular injury and disease

“…Generation and characterization of these sheep anti-rabbit glomerular antibodies, which bind selectively to podocytes, have been described previously (23,24). This experimental FSGS model induces an abrupt decline in podocyte number, which is associated clinically with proteinuria onset and histologically with FSGS (23,24). Disease was induced by administering 12.5 mg/20 g BW sheep anti-rabbit glomerular IgG antibodies in a single i.p.…”

“…GCaMP3 fluorescence in motile podocytes increased >10-fold in the UUO model over time (day 10 after UUO, 906 ± 142 AU; day 12, 2,746 ± 399 AU, P < 0.05 vs. day 10; day 16, 11,232 ± 1,422 AU, P < 0.05 vs. day 12; n = 5-15 glomeruli each; Figure 5C). Due to the rapidly developing pathology in the cytotoxic IgG-induced FSGS model (23,24), the present studies examined only the early changes through the first 4 days after induction. GCaMP3 fluorescence in clustering podocytes increased >2-fold over time (day 3 after induction, 3,811 ± 395 AU; day 4, 8,387 ± 332 AU, P < 0.05; n = 9-15 glomeruli each; Figure 5F).…”

Links between coagulation, inflammation, regeneration, and fibrosis in kidney pathology

“…134,135 Exaggerated mesenchymal healing as a predominant pathomechanism Mesangial regeneration upon injury can originate from several sources: surviving mesangial cells, from reninproducing cells of the extraglomerular mesangial, and from the bone marrow. [136][137][138][139][140] Mesangial repair upon mesangiolysis is often studied using the rat anti-Thy1.1 model. Mesangial hyperplasia is a hallmark of so-called 'mesangioproliferative' and 'membranoproliferative glomerulonephritis', a consequence of mesangial injury in the first place.…”