# PP2A as a drug target for diabetic kidney disease

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $589,487

## Abstract

Title: Role of PP2A in podocyte biology and diabetic kidney disease
SUMMARY
Diabetic kidney disease (DKD) remains a leading cause of chronic kidney disease with limited treatment options.
Arctigenin (ATG) is a major component derived from the extracts of Fructus Arctii, a traditional Chinese herbal
remedy that has shown to confer renoprotection and to reduce proteinuria in patients with DKD. Our preliminary
data show that ATG administration alone is sufficient to attenuate proteinuria and podocyte injury in mouse
models of type 1 and type 2 diabetes. Transcriptomic analysis of isolated glomeruli from the diabetic and control
mice showed that the major pathways affected by ATG treatment were of cell adhesion and inflammation. ATG
improved cell adhesion and inhibited migration in cultured human podocytes. By combining the Drug Affinity
Responsive Target Stability (DARTS) technique with Mass Spectrometry analysis we identified protein
phosphatase 2A (PP2A) as a top ATG-bound protein in cultured renal cells, and this was further confirmed by
western blot, computational docking, and surface plasmon resonance assay. In addition, ATG enhanced the
activity of PP2A in cultured podocytes and in diabetic glomeruli, resulting in dephosphorylation of p65 NF-κB.
Studying the PP2A interacting proteins in podocytes by Mass Spectrometry identified Drebrin-1 (DBN1) as a F-
actin interacting protein. Dephosphorylation of DBN1 at T335 by PP2A in podocytes resulted in increased cell
adhesion and decreased migration. Importantly, podocyte-specific deletion of Pp2a in mice led to aggravated
diabetes-induced podocyte and glomerular injury and the loss of efficacy in ATG-mediated renoprotection. In
addition, we found that PPP2R2B, a regulatory subunit of PP2A, expresses uniquely in podocytes in human
glomeruli. Its expression is downregulated in the glomeruli of human DKD. In human podocytes, the knockdown
of PPP2R2B reduced PP2A activity and expression of PPP2R2B is suppressed by high glucose. Phenome Wide
Association Scan identified several missense variants in the human PPP2R2B gene which were associated with
either worse or better renal outcomes. These data support a critical role of PP2A in human kidney disease.
Based on these observations, we hypothesized that PP2A plays a key role in podocyte biology and pathogenesis
of DKD. To test our hypothesis, we will determine the regulation and function of PPP2R2B in podocyte. We will
also study the role of PPP2R2B in the regulation of PP2A activity, subcellular localization, and podocyte function
in vitro under diabetic conditions and determine whether induction of PPP2R2B or its diseased variant expression
in podocytes affects podocyte injury and DKD progression in diabetic mice. We will also determine the
downstream signaling of PP2A in podocytes by focusing on the role of DBN1. We will study how PP2A affects
podocyte function through regulating DBN1 phosphorylation. The role of DBN1 and its phosphorylation will be
also ...

## Key facts

- **NIH application ID:** 10220959
- **Project number:** 5R01DK122980-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** John Cijiang He
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $589,487
- **Award type:** 5
- **Project period:** 2020-07-21 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220959

## Citation

> US National Institutes of Health, RePORTER application 10220959, PP2A as a drug target for diabetic kidney disease (5R01DK122980-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10220959. Licensed CC0.

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