Sethu Madhavan
Ohio State University, OH·Medicine & Clinical Research
Certain inherited versions of a gene called APOL1 (apolipoprotein L1) sharply raise the risk of chronic kidney disease, a condition in which the kidneys gradually lose their ability to filter blood. Two variants, known as G1 and G2, are among the strongest genetic risk factors known for several forms of kidney failure.
- Fields
Medicine & Clinical Research
Genetics
Physiology
- Topics
apolipoprotein L1
G1 and G2 risk variants
chronic kidney disease
- Grants
- 1 known grant, through Jun 2028
What they work on
- Define how ACOX1, the rate-limiting enzyme of peroxisomal fat breakdown, drives injury specific to the APOL1 G1 and G2 kidney risk variants, using overexpression plus gain- and loss-of-function manipulation in human podocytes.
- Map the physical interaction between APOL1 variants and ACOX1 at peroxisomes under low oxygen, and determine whether this binding raises ACOX1 levels and generates the reactive oxygen species that damage podocytes.
- Validate the proposed peroxisomal mechanism in human kidney biopsies of known APOL1 genotype, testing whether glomerular ACOX1 expression tracks with high-risk genotype and with focal segmental glomerulosclerosis.
- Test whether the ACOX1 inhibitor 10,12-tricosadiynoic acid (TDYA) restores peroxisomal homeostasis and reduces APOL1 variant toxicity in podocytes and in APOL1 transgenic mice challenged with the inflammatory signal interferon-gamma.
More about the research
Yet most people carrying them never develop progressive damage, which means the variants alone are not the whole story. The unanswered question is what makes the kidney's filtering cells vulnerable in some carriers and not others, particularly under everyday stresses such as low oxygen or inflammation.
Why it matters
Chronic kidney disease affects millions of Americans, and people carrying APOL1 G1 or G2 variants face aggressive forms of it with no treatment aimed at the underlying cause. Identifying ACOX1 and peroxisomal fat metabolism as the route from risk variant to cell injury would supply a concrete drug target. If blocking ACOX1 protects podocytes and APOL1 transgenic mice, it could support developing therapies that slow or prevent kidney damage in high-risk carriers.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Daniel Brennan
Johns Hopkins University, MD·Medicine & Clinical Research
Determine how donor APOL1 genotype affects time to graft failure, kidney function decline, acute rejection and proteinuria in recipients of kidneys from African American donors.
Kirk Campbell
University of Pennsylvania, PA·Physiology
Define how Hippo-YAP signaling regulates the calcium-activated potassium channel KCa3.1 in podocytes, including whether nuclear YAP protects the actin cytoskeleton by repressing the KCNN4 gene that encodes it.
Radhika Muzumdar
University of Pittsburgh, PA·Physiology
Determine how effectively humanin, a small peptide encoded in mitochondria, protects the heart in mouse models of myocardial ischemia-reperfusion injury and ischemia-induced heart failure in aging, measuring infarct size and cardiac function.
The school
Ohio State University: 71 labs on PI Pages, $1.6B a year on research, 882 research doctorates a year.
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