Mechanism of cystogenesis by Cd79a-driven, conditional mTOR activation in developing mouse nephrons

Abstract

Polycystic kidney disease (PKD) is a common genetic disorder arising from developmental and postnatal processes. Defects in primary cilia and their signaling (eg, mTOR) underlie the pathogenesis. However, how mTOR regulates tubular integrity remains unclear. The paucity of faithful models has limited our understanding of pathogenesis and, therefore, the refinement of therapeutic targets. To understand the role of mTOR in early cystogenesis, we studied an in-house mouse model, Cd79a-Cre;Tsc1ff. (Cd79a-Tsc1 KO hereafter), recapitulating human autosomal-dominant PKD histology. Cre-mediated Tsc1 depletion driven by the promoter for Cd79a, a known B-cell receptor, activated mTORC1 exclusively along the distal nephron from embryonic day 16 onward. Cysts appeared in the distal nephron at 1 weeks of age and mice developed definite PKD by 4 weeks. Cd79a-Tsc1 KO tubule cells proliferated at a rate comparable to controls after birth but continued to divide even after postnatal day 14 when tubulogenesis is normally completed. Apoptosis occurred only after 9 weeks. During postnatal days 7–11, pre-cystic Cd79a-Tsc1 KO tubule cells showed cilia elongation, aberrant cell intercalation, and mitotic division, suggesting that defective cell planar polarity (PCP) may underlie cystogenesis. mTORC1 was activated in a portion of cyst-lining cells and occasionally even when Tsc1 was not depleted, implying a non-autonomous mechanism. Our results indicate that mTORC1 overactivation in developing distal tubules impairs their postnatal narrowing by disrupting morphogenesis, which orients an actively proliferating cell toward the elongating axis. The interplay between mTOR and cilium signaling, which coordinate cell proliferation with PCP, may be essential for cystogenesis.

Novel Potential Therapeutic Targets in Autosomal Dominant Polycystic Kidney Disease from the Perspective of Cell Polarity and Fibrosis

“…Renal cysts in ADPKD originate from the abnormal proliferation and incomplete differentiation of tubule cells and exhibit disruptions in cell polarity, including alterations in apical-basal polarity and extracellular matrix rearrangements ( Calvet, 1993 ; Kunimoto et al ., 2017 ; Xu et al ., 2018a ). Numerous cellular abnormalities, including cell polarity disruption, have been observed in the cyst-lining cells during cyst growth ( Arkhipov and Pavlov, 2019 ; Tran Nguyen Truc et al ., 2023 ). The role of these disruptions has been discussed previously ( Sharma et al ., 2019 ).…”

“…Therefore, ADPKD may be associated with cell polarity problems. Studies related to cell polarity are essential for understanding the intrinsic properties of ADPKD, the process of renal cyst formation and growth, and potential therapeutic strategies ( Tran Nguyen Truc et al ., 2023 ). Research on cell polarity is currently underway to elucidate the intracellular processes and molecular mechanisms contributing to ADPKD and is expected to aid in the development of effective treatment strategies.…”

Autosomal Dominant Polycystic Kidney Disease: Is There a Role for Autophagy?

“…The mTOR signaling pathway, which affects both autophagy and cilium signaling, is critical in cystogenesis [74]. In PKD cells with short cilia, mTOR is activated, and autophagy is repressed.…”