The goal of this proposal is to prove that in proteinuric glomerular diseases, the leading cause of chronic and endstage kidney disease, cells of renin lineage (abbreviated CoRL) normally residing in the juxta-glomerular compartment, serve as progenitors which restore glomerular epithelial cell number. Injury to glomerular visceral epithelial cells (aka podocytes) in proteinuric glomerular diseases oftentimes leads to a decrease in cell number, which directly underlies the development of progressive glomerular scarring and declining kidney function. A fundamental limitation to the repair process is the inability of terminally differentiated podocytes to adequately regenerate and replace those lost due to disease. Thus, an ideal clinical therapeutic intervention is to restore/normalize podocyte number to prevent/limit scarring. Recent studies show that neighboring glomerular parietal epithelial cells (PECs) might serve as a source to replace podocytes in disease. However, proof that PECs become fully functioning podocytes is still lacking. The purpose of this proposal is to study this existing problem in a completely new context. CoRL are the only source of active circulating renin normally, and thus are critical regulators of vascular tone and RAAS activation. However, we and others have reported that CoRL exhibit marked plasticity and stemness, serving as progenitors for glomerular epithelial cells, vascular smooth muscle cells and mesangial cells, and can also transdifferentiate into EPO-producing cells. In 3 different strains o CoRL reporter transgenic mice that specifically fate map CoRL with a permanent fluorescent reporter, we showed that CoRL undergo juxta- to intra- glomerular migration following an abrupt decline in podocyte number in experimental FSGS. Once within the glomerulus they begin to co-express two PEC specific proteins and four podocyte specific proteins. The overall objective of this grant proposal is to test the hypothesis that CoRL, and cells derived from their lineage, serve as progenitors to replace lost PECs and podocytes in disease.
Aim 1 will define the migration of CoRL into the glomerulus in tamoxifen-inducible CoRL reporter mice in a second model of FSGS (remnant kidney) by combining cell fate-mapping with PEC and podocyte markers and morphophysiological assessment. Clonality of CoRL transdifferenting into podocytes and PECs will be determined in inducible multi-reporter (confetti) mice, activated by the renin gene.
Aim 2 will test the hypothesis that the regeneration of glomerular epithelial cells by CoRL progenitors is reparative, using titrated ablation of CoRL in CoRL-specific diptheria toxin receptor mice that we have generated.
Aim 3 will extend our genome-wide microarray characterization of FACS-sorted CoRL in normal mice by defining critical genes necessary for CoRL transition into glomerular epithelial cell progenitors regulating their differentiation, migration and proliferation in experimental FSGS. Using these innovative approaches, we anticipate that the results will provide compelling evidence for a new paradigm in proteinuric glomerular disease in which CoRL are novel reparative progenitors which replace injured PECs and podocytes.

Public Health Relevance

The purpose of this proposal is to study the existing problem of age-related podocyte depletion in a completely new context. The goal is to prove that with advancing age, kidney regeneration, and thus repair, is inadequate because progenitors are unable to replace and restore glomerular podocytes. We anticipate that the results will provide compelling evidence for a new paradigm in aging kidneys in which recently identified progenitors are unable to adequately regenerate to replace podocytes, which leads to glomerulosclerosis and reduced kidney function.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pathobiology of Kidney Disease Study Section (PBKD)
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Hoshizaki, Deborah K
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Stefanska, Ania; Eng, Diana; Kaverina, Natalya et al. (2016) Cells of renin lineage express hypoxia inducible factor 2α following experimental ureteral obstruction. BMC Nephrol 17:5
Lichtnekert, Julia; Kaverina, Natalya V; Eng, Diana G et al. (2016) Renin-Angiotensin-Aldosterone System Inhibition Increases Podocyte Derivation from Cells of Renin Lineage. J Am Soc Nephrol 27:3611-3627
Zhang, Jiong; Yanez, David; Floege, Anna et al. (2015) ACE-inhibition increases podocyte number in experimental glomerular disease independent of proliferation. J Renin Angiotensin Aldosterone Syst 16:234-48
Stefanska, Ania; Eng, Diana; Kaverina, Natalya et al. (2015) Interstitial pericytes decrease in aged mouse kidneys. Aging (Albany NY) 7:370-82
Nakagawa, Naoki; Xin, Cuiyan; Roach, Allie M et al. (2015) Dicer1 activity in the stromal compartment regulates nephron differentiation and vascular patterning during mammalian kidney organogenesis. Kidney Int 87:1125-40
Eng, Diana G; Sunseri, Maria W; Kaverina, Natalya V et al. (2015) Glomerular parietal epithelial cells contribute to adult podocyte regeneration in experimental focal segmental glomerulosclerosis. Kidney Int 88:999-1012
Pippin, Jeffrey W; Kaverina, Natalya V; Eng, Diana G et al. (2015) Cells of renin lineage are adult pluripotent progenitors in experimental glomerular disease. Am J Physiol Renal Physiol 309:F341-58
Gomez, Ivan G; MacKenna, Deidre A; Johnson, Bryce G et al. (2015) Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways. J Clin Invest 125:141-56
Roeder, Sebastian S; Stefanska, Ania; Eng, Diana G et al. (2015) Changes in glomerular parietal epithelial cells in mouse kidneys with advanced age. Am J Physiol Renal Physiol 309:F164-78
Naito, Shokichi; Pippin, Jeffrey W; Shankland, Stuart J (2014) The glomerular parietal epithelial cell's responses are influenced by SM22 alpha levels. BMC Nephrol 15:174

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