Podocyte injury is a major cause of kidney diseases, for which specific treatments are lacking. Many animal studies suggest that retinoid acid (RA) protects against podocyte injury. The effect of RA on podocytes, however, is not fully understood and the clinical utility of RA for the treatment of kidney disease is limited by its significant side effects. Podocyte proliferation is found in collapsing focal segmental glomerulosclerosis (FSGS) in HIV-associated nephropathy and crescentic glomerulonephritis (GN). Podocyte loss occurs in classic FSGS. Recent studies suggest that parietal epithelial cells (PECs) are present predominantly in cellular crescents of GN and collapsing FSGS and could function as the progenitor cells for podocytes. During the last funding period, we found that RA inhibits proliferation and restores the expression of differentiation markers in HIV- infected podocytes. The effects of RA are likely mediated by retinoic acid receptor alpha (RARA) based on both in vitro and in vivo studies. We identified a new class of RARA agonist which exhibits the same renal protection as RA but has minimal side effects. We also identified KLF15 as a new downstream transcription factor that mediates RA-induced podocyte differentiation. Our recent data suggest that RA improves renal function and reduces the number of crescents in nephrotoxic serum-induced GN model (NTS-GN). RA also increases the expression of podocyte markers in PECs of GN mice and may stimulate the transdifferentiation of PECs into podocytes based on the lineage tracing studies. In addition, our collaborator (Kretzler lab) examined the RNAseq data of kidney biopsies from the NEPTUNE core dataset and found that RA signaling is markedly altered in human diseased kidneys. Based on these novel findings, we and we will test the following specific aims:
Specific aim 1 : We will perform lineage tracing of podocyte and PEC to determine whether RA confers renal protection against NTS- GN and adriamycin-induced nephropathy (ADRN) by restoring the differentiation of injured podocytes and/or inducing the transdifferentiation of PECs into podocytes. NTS-GN is a glomerular epithelial cell proliferative model whereas ADRN, a model of FSGS, is characterized by podocyte loss.
Specific aim 2 : We will assess the development of NTS-GN and ADRN in animals with podocyte-specific RARA knockout and characterize the therapeutic potential of a new class of RARA agonist (i.e. BD4) in these 2 models.
Specific aim 3 : We will determine how KLF15 mediates the effects of RA on disease progression and podocyte injury.
Specific aim 4 : We will assess whether RA treatment of these mice is able to restore the pattern of genes and pathways altered in human disease using the cross-species mapping strategies developed by the Kretzler lab and confirm the expression of genes and activation of signaling pathways identified to be differentially regulated by RA as well as altered in human kidney diseases. We will also validate expression of RA signaling molecules in kidney biopsies from patients with glomerular disease by immunostaining in collaboration with Dr. D'Agati.

Public Health Relevance

Glomerular disease with podocyte injury is a major cause of end stage renal disease. Thus, new therapy targeting podocytes will have enormous clinical value. The proposed studies will help us to determine whether drugs activating retinoic acid pathway could be developed to treat patients with glomerular disease by preventing or reversing podocyte injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK078897-06A1
Application #
8629485
Study Section
Special Emphasis Panel (ZDK1-GRB-C (O1))
Program Officer
Rys-Sikora, Krystyna E
Project Start
2007-08-01
Project End
2018-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
6
Fiscal Year
2014
Total Cost
$468,437
Indirect Cost
$169,958
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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