Marneros: Discover key structures in kidney formation
01 July 2020
Renal fibrosis is a direct consequence of the kidney’s limited capacity to regenerate after injury. Renal scarring results in a progressive loss of renal function, ultimately leading to end-stage renal failure and a requirement for dialysis or kidney transplantation.
A new study reports the discovery of how key structures in the kidney are formed and how the structures may play an important role in treating renal fibrosis. Their study, “AP-2β/KCTD1 Control Distal Nephron Differentiation and Protect against Renal Fibrosis,” was published in Developmental Cell and led by Alexander G. Marneros, MD, PhD, a physician and scientist at Massachusetts General Hospital’s Cutaneous Biology Research Center.
Marneros and his colleagues were previously studying families affected by a rare skin condition called Scalp-Ear-Nipple (SEN) syndrome. The team found that the syndrome is caused by a mutation in a gene called KCTD1, and that mice bred to lack the KCTD1 gene developed severe renal fibrosis and kidney failure. They also observed that patients with KCTD1 mutations in the SEN syndrome families also developed chronic kidney disease (CKD) with renal fibrosis. “This raises the question of what the physiological function of this gene is,” stated Marneros.
Their previous finding prompted them to explore the function of the gene. In the new study, they found the protein known as transcription factor AP-2 beta induces expression of KCTD1 in kidney structures called distal convoluted tubules (DCTs).DCTs play a critical role in a variety of homeostatic processes, including sodium chloride reabsorption, potassium secretion, and calcium and magnesium handling. DCTs form from progenitor cells in the developing kidney in a process called differentiation, but the genes that controlled this process was not previously known. Marneros found that the protein AP-2 beta is critical to forming early-stage DCTs. Without the protein, DCTS are not formed.
“The developmental mechanisms that orchestrate differentiation of specific nephron segments are incompletely understood, and the factors that maintain their terminal differentiation after nephrogenesis remain largely unknown. Here, the transcription factor AP-2β is shown to be required for the differentiation of distal tubule precursors into early stage distal convoluted tubules during nephrogenesis. In contrast, its downstream target KCTD1 is essential for terminal differentiation of early stage DCTs into mature DCTs, and impairment of their terminal differentiation owing to lack of KCTD1 leads to a severe salt-losing tubulopathy.”
The mice’s ability to reabsorb salt from urine was impaired and led to excessive urine production when KCTD1 was inactivated, which showed the KCTD1 gene needed for a DCT to maintain its function throughout adulthood.
“Moreover, sustained KCTD1 activity in the adult maintains mature DCTs in this terminally differentiated state and prevents renal fibrosis by repressing β-catenin activity, whereas KCTD1 deficiency leads to severe renal fibrosis. Thus, the AP-2β/KCTD1 axis links a developmental pathway in the nephron to the induction and maintenance of terminal differentiation of DCTs that actively prevents their de-differentiation in the adult and protects against renal fibrosis. Importantly, this study revealed that kidneys of adult mice lacking the KCTD1 gene showed increased activation of a protein called beta-catenin. Beta-catenin is essential for proper kidney development, but is normally suppressed in the adult kidney,” wrote the researchers.
Genetic tools were used to reduce the beta-catenin reactivation in the adult kidney and blocked renal fibrosis and deterioration of kidney function in the mice without the KCTD1 gene.
This study gives a better understanding and closer look into how the kidney functions. “The results suggest that therapeutic approaches to block reactivation of beta-catenin or related molecules in the adult kidney could inhibit renal fibrosis,” explained Marneros.
Published by genengnews.com on June 19, 2020
Image by Shutterstock