The heterogeneous cellular composition of the mammalian renal collecting duct enables regulation of fluid, electrolytes, and acid-base homeostasis, but the molecular mechanism of its development has yet to be elucidated. The Notch signaling pathway is involved in cell fate determination and has been implicated in proximal-distal patterning in the mammalian kidney. To investigate the role of Notch signaling in renal collecting duct development, we generated mice in which Mind bomb-1 (Mib1), an E3 ubiquitin ligase required for the initiation of Notch signaling, was specifically inactivated in the ureteric bud of the developing kidney. Mice lacking Mib1 in the renal collecting duct displayed increased urinary production, decreased urinary osmolality, progressive hydronephrosis, sodium wasting, and a severe urinary concentrating defect manifested as nephrogenic diabetes insipidus. Histological analysis revealed a diminished number of principal cells and corresponding increase in the number of intercalated cells. Transgenic overexpression of Notch intracellular domain reversed the altered cellular composition of mutant renal collecting duct, with principal cells occupying the entire region. Our data demonstrate that Notch signaling is required for the development of the mammalian renal collecting duct and principal cell differentiation and indicate that pathway dysregulation may contribute to distal renal tubular disorders.

Our present results support that autophagy induced by UUO has a renoprotective role in the obstructed kidney and regulatory role of compensatory cellular proliferation in the contralateral kidney through Akt-mTOR signalling pathway.

The tissue distribution of silver (Ag) nanoparticles showed a dose-dependent accumulation of Ag in all the tissues examined, including testes, kidneys, liver, brain, lungs, and blood. However, a gender-related difference in the accumulation of Ag was noted in the kidneys, with a twofold higher concentration in female kidneys compared males after subacute exposure to Ag nanoparticles via inhalation or oral ingestion. To investigate the gender-specific accumulation of Ag nanoparticles in kidneys of Fischer 344 rats, detailed histopathological studies were conducted by Ag enhancement staining. Female rats showed a higher accumulation of Ag nanoparticles in all kidney regions, including cortex, outer medulla, and inner medulla. In particular, the glomerulus in the cortex contained a higher accumulation in females than males. The Ag nanoparticles were also preferentially accumulated in the basement membranes of the renal tubules in the cortex, middle and terminal parts of the inner medulla, and outer medulla. In addition, Ag nanoparticles were detected in the cytoplasm and nuclei of interstitial cells in the inner medulla of the kidney.

The accumulation of extracellular matrix proteins in the interstitial area is the final common feature of chronic kidney diseases. Accumulating evidence suggests that transforming growth factor (TGF)-b1 promotes the development of renal fibrosis. Heat shock protein (Hsp) 90 inhibitors have been shown to repress TGF-b1 signaling, but whether they inhibit renal fibrosis is unknown. The purpose of this study is to determine the therapeutic efficacy of Hsp90 inhibitor on renal fibrosis. In TGF-b1-treated HK2 cells and unilateral ureteral obstruction (UUO) kidneys, we found that 17-allylamino-17-demethoxygeldanamycin (17AAG), an Hsp90 inhibitor, decreased the expression of a-smooth muscle actin, fibronectin, and collagen I and largely restored the expression of E-cadherin. 17AAG inhibited TGF-b1-mediated phosphorylation of Smad2, Akt, glycogen synthase kinase-3b, and extracellular signal-regulated kinase in HK2 cells. Inhibition of Hsp90 also blocked TGF-b1-mediated induction of snail1. This 17AAG-induced reduction was completely restored by simultaneous treatment with proteasome inhibitor MG132. Furthermore, 17AAG blocked the interaction between Hsp90 and TGF-b type II receptor (TbRII) and promoted ubiquitination of TbRII, leading to the decreased availability of TbRII. Smurf2-specific siRNA reversed the ability of 17AAG to inhibit TGF-b1 signaling. The effect of 17AAG on TbRII expression and renal fibrosis was confirmed in UUO kidneys. These findings suggest that Hsp90 inhibitor prevents the development of renal fibrosis via a mechanism dependent on Smurf2-mediated degradation of TbRII.

Renal tubulointerstitial fibrosis (TIF) is the final pathway of various renal injuries that result in chronic kidney disease. The mammalian Hippo-Salvador signaling pathway has been implicated in the regulation of cell proliferation, cell death, tissue regeneration, and tumorigenesis. Here, we report that the Hippo-Salvador pathway plays a role in disease development in patients with TIF and in a mouse model of TIF. Mice with tubular epithelial cell (TEC)-specific deletions of Sav1 (Salvador homolog 1) exhibited aggravated renal TIF, enhanced epithelial-mesenchymal transition-like phenotypic changes, apoptosis, and proliferation after unilateral ureteral obstruction (UUO). Moreover, Sav1 depletion in TECs increased transforming growth factor (TGF)-β and activated β-catenin expression after UUO, which likely accounts for the abovementioned enhanced TEC fibrotic phenotype. In addition, TAZ (transcriptional coactivator with PDZ-binding motif), a major downstream effector of the Hippo pathway, was significantly activated in Sav1-knockout mice in vivo. An in vitro study showed that TAZ directly regulates TGF-β and TGF-β receptor II expression. Collectively, our data indicate that the Hippo-Salvador pathway plays a role in the pathogenesis of TIF and that regulating this pathway may be a therapeutic strategy for reducing TIF.