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Podocyte-to-parietal epithelial cell signal by exosomes drives proliferative glomerulopathy

Award Number: R01DK147153
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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Podocyte-to-parietal epithelial cell signal by exosomes drives proliferative glomerulopathy - Project Summary: Parietal epithelial cells (PECs) line Bowman’s capsule and neighbor podocytes on the opposite side of Bowman’s space without any physical barriers separating the two cell populations. In proliferative glomerulopathies such as rapidly progressive glomerulonephritis (RPGN), the most aggressive form of acquired glomerular disease, podocyte injury leads to the pathogenic activation and unchecked proliferation of PECs. This causes an agglomeration of activated PECs within Bowman’s space causing crescent formation, which contributes directly to disease progression and severity. Although severe podocyte injury is the initiating insult in all forms of proliferative glomerulopathy, how injured podocytes communicate with PECs to induce their activation is not well understood. To investigate whether this podocyte-to-PEC crosstalk is mediated by podocyte-derived exosomes, we induced nephrotoxic serum nephritis (NTSN), a widely used mouse model of RPGN, in podocyte-specific exosome reporter mice. In this model, podocyte-derived exosomes carry a GFP- tag which allows them to be tracked and to identify uptake by recipient cells. In this way, we identify activated PECs as the major kidney recipient cell type for podocyte-derived exosomes in NTSN. Pharmacological inhibition of exosomes in NTSN mice reduced PEC activation, crescent formation, and proteinuria. Furthermore, treatment of cultured PECs with urinary exosomes derived from NTSN mice caused increased proliferation and expression of PEC activation markers, whereas urinary exosomes from control mice had the opposite effects. Taken together, these findings suggest that podocyte-derived exosomes contribute to PEC activation. To identify responsible podocyte-derived exosomal cargo miRNAs, we performed small-RNA sequencing of podocyte-derived exosomes isolated from the urine of NTSN and control mice. Quantitative PCR of glomeruli and urinary exosomal pellets validated that upregulated miRNAs were increased in the NTSN model. One of the most upregulated miRNA cargoes was miR-155, an oncogenic miRNA, whose role in proliferative GN is unknown. Gain-of-function studies in cultured PECs shows that miR-155 is sufficient to drive PEC activation. We hypothesize that a direct podocyte-to-PEC signal mediated by uptake of podocyte- derived exosomes by PECs drives PEC activation in proliferative glomerulopathy and that exosomal cargo miR-155 is a key driver of the PEC activated phenotype. We propose three specific aims: 1) We will validate that uptake of podocyte-derived exosomes by PECs is central to PEC activation in NTSN. 2) We will determine the role of podocyte-derived exosomal miR-155 cargo in mediating PEC activation in NTSN. 3) We will characterize the role of podocyte-derived exosomal cargo miRNAs in human proliferative glomerulopathy. Overall, the goal of this proposal is to establish podocyte-to PEC signaling by exosomes as a major cause of PEC activation and in this way, to identify potentially druggable targets to treat or prevent proliferative glomerulopathy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $816,825 )
2026	2026	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/17/2026	NEW	$816,825
														Subtotal = $816,825

Grand Total All Awards = $816,825

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Podocyte-to-parietal epithelial cell signal by exosomes drives proliferative glomerulopathy

Award Number: R01DK147153

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/15/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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