Cheng to expand understanding of renal tubular disorders

Chih-Jen Cheng, MD, associate professor in Nephrology and Hypertension, has received a five-year, $1.55M R01 from the US Department of Health and Human Services. With these funds, Cheng will produce greater insight into the pathogenesis of Bartter syndrome (BS), a rare genetic disorder resulting in kidney dysfunction. Children diagnosed with BS have difficulty reabsorbing salt through the kidneys, which creates electrolyte and fluid imbalances in the body. Symptoms of BS can include salt-craving, polyuria, weakness, and dehydration. All of this can also lead to growth restriction and chronic kidney disease.

In previous work, Cheng has challenged the conventional understanding that salt wasting in BS is due to the loss of function of transporters in the mature thick ascending limb of Henle’s loop (TAL), a segment of renal tubule enriched with mitochondria and active salt transport. Instead, he and colleagues have recently reported that type III BS, caused by mutations in a specific chloride channel, CIC-K2, is connected to developmental defects in the kidney’s inner medulla and underdeveloped TAL. What is unknown is why chloride channel deficiency leads to tubule hypoplasia.

With this new grant, Cheng will use mouse models with genetically manipulated transport activity of renal tubules to study how transport activity regulates mitochondrial function and cell proliferation in renal tubules. Cheng hypothesizes that CIC-K2 deficiency, which is known to disrupt the active salt transport across TAL, could reduce energy demand, further downregulating mitochondrial bioenergetics/biogenesis and cell proliferation. Cheng hopes this project can decipher not only the pathogenesis of BS but also the elusive mechanisms of disuse atrophy (or use hypertrophy) of renal tubules.

Current treatment for BS is mainly dietary salt supplements, yet 25% of BS children still develop chronic kidney disease in early adulthood. Cheng hopes that with a fundamental understanding of the cell biology of renal tubules, he can improve treatments and outcomes for patients with BS or other renal tubular disorders.

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