Abstract: SA-PO612
Role and Mechanism of mTOR Signaling Activation in Nephronophthisis Type I
Session Information
- Cystic Kidney Diseases: Genetic Causes, Modifiers, and Extrarenal Manifestations
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic
Authors
- Sun, Liangzhong, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China
- Zou, Baojuan, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China
- Wang, Qianying, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China
Background
Nephronophthisis (NPH) , a group of autosomal recessive ciliopathies, is a lead- ing genetic cause of renal failure in children and adolescents. Over 20 NPH genes have been identified, among which NPHP1 is the most frequent. It is generally believed that dysfunctional ciliary signa- ling leads to uncontrolled cellular growth and proliferation by activating the mTOR signaling, which leads to organ cystogenesis such as polycystic kidney disease (PKD). However, NPH is prominently featured by extensive tubular atrophy and interstitial fibrosis, whereas its cystic load are relatively mild. Hence, it’s of great interest whe- ther abnormal ciliary signaling in NPH activates mTOR signaling along with cell proliferation similar to PKD.
Methods
In this study, wild-type and NPHP1-knockout (NPHP1-/-) MDCK cells, an well as mice, are used to explore the role of mTOR signaling in NPH and figure out whether mTOR inhibition can rescue renal lesions in NPH type I.
Results
NPHP1 deletion activates mTOR signaling in MDCK cells and mouse kidneys, featured by a significant increase of p-S6/S6 and p-4EBP1/4EBP1. Expression of Deptor, a natural mTOR inhibitor, declines singularly with NPHP1 deletion in vitro and in vivo. Proliferation decreased in NPHP1-/- cells and mRNA analysis showed an alteration in p21, with a 1-fold higher expression compared with wild-type. Knockdown of Deptor, which activates mTOR signaling, promotes proliferation in wild-type but not in NPHP1-/- MDCK cells. p21 expression was induced in NPHP1-/- but suppressed in wild-type MDCK cells by Deptor-siRNA. NPHP1-/- MDCK cells shows increased resistance to rapamycin, which further reduces Deptor expression. Rapamycin alleviates renal fibrotic, cystic, and inflammatory lesions of NPHP1-/- mice and improves their renal function. However, it brings about adverse effects, including loss of weight gain and aggravated cell senescence in kidney.
Conclusion
mTOR signaling is excessively activated in renal tubular cells of NPH type I, due to a decreased expression of Deptor. Despite mTOR activation, NPHP1 deficiency restrains proliferation in renal tubular cells. Rapamycin significantly alleviates renal fibrotic, cystic and inflammatory lesions and improves renal function of NPHP1-/- mice. However, adverse effects include loss of weight gain and aggravated cell senescence of kidney in rapamycin treatment.
Funding
- Government Support – Non-U.S.