# Megalin, and transition from AKI to CKD

> **NIH VA I01** · MICHAEL E DEBAKEY VA MEDICAL CENTER · 2024 · —

## Abstract

The prevalence of chronic kidney disease (CKD) in the US is rising concomitant with aging of the general
population and coexistence of comorbidities such as hypertension and diabetes mellitus. Cardiovascular
outcomes, sudden death and overall mortality are worse with advancing CKD. Ischemic kidney injury may
exacerbate other disease processes and accelerate the progression to ESKD. The underlying pathways and
contributing factors to the development and progression from AKI to CKD are poorly understood. Abnormalities in
mitochondrial function play critical roles in many disease processes. We have recently shown megalin is present
in the mitochondria, where it associates with stanniocalcin-1 (STC1) and SIRT3; two proteins that promote anti-
oxidant defenses. Internalization into the cell and shuttling of the intracrines angiotensin II, STC1 and TGF-β1 from
the cell surface to the mitochondria are megalin-dependent; deletion of megalin is associated with impaired
mitochondrial respiration and glycolysis. Megalin is found in clathrin-coated pits and provides endocytic receptor-
mediated ligand uptake. Here, we show tubular epithelium-specific KO of megalin aggravates AKI after
ischemia/reperfusion (I/R) and is associated with severe and sustained kidney inflammation, upregulation of TGF-
β1 and fibrosis, cell cycle arrest, mitochondrial stress, dysregulated lysosomal function and rapid progression to
CKD. Additionally, we show TGF-β1 is degraded by the mitochondrial caseinolytic protein proteases. We
hypothesize that megalin is a guardian of kidney health; megalin downregulates pathways of cellular
injury (inflammation, TGF-β1, fibrosis) and preserves recovery pathways (mitochondrial function,
lysosomal biogenesis); upregulation of megalin may be a therapeutic target to slow CKD progression.
Aim 1A will examine kidney injury, TGF-β1 signaling, fibrosis and progression to CKD in mice with tubular
epithelium-specific overexpression of megalin using post-I/R model. Aim 1B will examine the role of mitochondrial
caseinolytic protein proteases in the termination of TGF-β1 signaling. Aim 1C will examine the expression of cell
cycle regulators and TGF-β1 signaling after I/R in mice with combined conditional tubular epithelium specific
deletion of megalin and SMAD3. Aim 2 will examine the expression of signaling molecules involved in autophagy
and lysosomal biogenesis (mTOR, PGC1α, TFEB, ERK2 and calcineurin) and characterize lysosomal morphology
following hypoxia/reoxygenation in sgScramble and sgLrp2 BUMPT cells. This proposal will examine new
paradigms for megalin-mediated kidney protection and identify therapeutic targets to prevent CKD progression
after ischemic AKI.

## Key facts

- **NIH application ID:** 10702038
- **Project number:** 2I01BX002006-09A1
- **Recipient organization:** MICHAEL E DEBAKEY VA MEDICAL CENTER
- **Principal Investigator:** DAVID SHEIKH-HAMAD
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2014-04-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10702038

## Citation

> US National Institutes of Health, RePORTER application 10702038, Megalin, and transition from AKI to CKD (2I01BX002006-09A1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10702038. Licensed CC0.

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