# SMPDL3b and podocyte insulin signaling in DKD

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2020 · $345,375

## Abstract

ABSTRACT
Diabetic kidney disease (DKD) is the most common single cause of end stage kidney disease in the USA.
Disruption of physiological insulin signaling occurs in glomeruli and podocytes in DKD, and podocyte-specific
deficiency of insulin receptor (IR) recapitulates many features of DKD. Two isoforms of the IR have been
described that either lack (IRA) or contain (IRB) the 12 amino acids encoded by exon 11. IRA signals primarily
through p70S6K while IRB signals primarily through Akt, an important survival factor in podocytes. The cause
of altered insulin signaling observed in podocytes in DKD as well as the relative contribution of IRA and IRB
signaling to podocyte function remains to be established. Podocytes are dependent on functional lipid rafts for
proper signaling and survival, and lipid rafts affect primarily IRB signaling. Although the raft-associated protein
caveolin-1 (cav-1) binds IR and modulates IR-dependent signaling, little is known about how lipid rafts
influence IR specific isoform signaling.
We have identified sphingomyelin-phosphodiesterase-acid-like-3b (SMPDL3b) as a novel enzyme expressed
in podocyte lipid rafts and upregulated in DKD. Our preliminary data show that SMPDL3b differentially affects
IRA/IRB signaling by disrupting the interaction of IRB with Cav1 and facilitating IRA binding to Cav1. The
SMPDL3b protein contains a phosphodiesterase-like domain that allows SMPDL3b to form complexes with
Cav1 and a phosphatase-like domain that converts ceramide-1-phosphate (C1P) to ceramide. However, the
mechanisms linking SMPDL3b overexpression to podocyte altered IR signaling in DKD remain unknown.
Based on these observations, we hypothesize that SMPDL3b suppresses IRB/Cav1 interaction by
converting C1P to ceramide, and that podocyte-specific SMPDL3b deletion or C1P replacement are
sufficient to prevent podocyte injury in DKD. We will determine in Aim 1 if SMPDL3b differentially affects
IRA/IRB localization and function in podocyte lipid rafts. Aim 2 will investigate if SMPDL3b deficiency protects
from podocyte injury in experimental mouse models of DKD and in Aim 3, we will explore if C1P replacement
is sufficient to restore IR signaling and to protect from DKD. This proposal is significant, as it will help our
understanding of the mechanisms by which sphingolipids may regulate insulin receptor (IR) signaling in
podocytes as well as other cell types. This proposal is innovative as it may support the development of a C1P
lipid replacement strategy for the cure of patients affected by DKD.

## Key facts

- **NIH application ID:** 9879633
- **Project number:** 5R01DK117599-03
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** ALESSIA FORNONI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $345,375
- **Award type:** 5
- **Project period:** 2018-03-12 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879633

## Citation

> US National Institutes of Health, RePORTER application 9879633, SMPDL3b and podocyte insulin signaling in DKD (5R01DK117599-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9879633. Licensed CC0.

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