Key Steps In Kidney Development Identified By Researchers
According to a new study by a researcher at Massachusetts General Hospital (MGH), understanding how certain features are formed in the kidneys can provide crucial insights for treating renal fibrosis (or scarring), a feature of chronic kidney disease (CKD).
A previous study on the genetic origins of a rare skin disorder, Scalp-Ear-Nipple (SEN) syndrome, led to these new findings published in the journal Developmental Cell on June 17, 2020. A team led by Alexander G. Marneros, MD, Ph.D., a physician-scientist at Mass General’s Cutaneous Biology Research Center, examined families affected by this skin disorder.
They found a mutation in a gene called KCTD1 is responsible for this syndrome. Byt very little is known about the gene. Marneros, the author of the Developmental Cell paper, said this raised a question of what the physiological function of this gene is.
To his surprise, the mice that lacked the KCTD1 gene were found to develop severe renal fibrosis and kidney failure. Patients in the Scalp-Ear-Nipple syndrome families, who also have a mutation in the KCTD1 gene, developed CKD with renal fibrosis.
Marneros showed that expression of KCTD1 in kidney structures called distal convoluted tubules (DCTs
) is induced by a protein known as transcription factor AP-2 beta.DCTs play a major role in preventing excessive urine production by facilitating reabsorption of salt from urine. During the development of the kidney, DCTs are developed from the differentiation of progenitor cells. It was previously unknown, which genes control this differentiation process that leads to the development of fully functional DCTs.
Marneros found that the key to forming early-stage DCTs is the protein AP-2 beta. He said DCTs are not formed in the absence of AP-2 beta. Once the DCTs are formed during the kidney development, the second set of differentiation processes is triggered by the expression of KCTD1, which induced by AP-2 beta.
But the differentiation of early-stage DCTs into mature DCTs is blocked by the inactivation of KCTD1 in mice. This leads to impairment in the reabsorption of salt from urine, causing excessive urine production. KCTD1 gene is also essential for DCT to maintain its function throughout adulthood.
Importantly, increased activation of a protein called beta-catenin was observed in the kidneys of adult mice lacking the KCTD1 gene. Beta-catenin is normally suppressed in the adult kidney, though it’s crucial for proper kidney development. Cyst formation and renal fibrosis were promoted in mice as they aged, due to this abnormal reactivation of beta-catenin. Reducing the beta-catenin reactivation in the adult kidney using genetic tools inhibited deterioration of kidney function and renal fibrosis in mice, without the KCTD1 gene.
Fundamental questions about the key steps in kidney development, like how DCTs form and mature, are answered by this study. The results demonstrate that renal fibrosis can be inhibited using therapeutic approaches to block reactivation of beta-catenin or related molecules in the kidney.
