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Renal Collecting Duct Cell‐specific mVps34 Deletion Decreases Nephron Number and Increases Nephron Size
Author(s) -
Chen JianKang,
Hu Bo,
Chen Jianchun
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.705.11
Subject(s) - nephron , medicine , endocrinology , glomerulosclerosis , kidney , renal medulla , renal function , biology , proteinuria
The class III PI3‐kinase, mVps34, has been implicated in autophagy and endocytosis, but its physiological role in the renal collecting duct system is unknown. We generated an mVps34 gene‐floxed mouse and crossed it with Hoxb7‐Cre mice to produce collecting duct‐specific mVps34 knockout mice ( mVps34 cdKO , KO) and used mVps34 flox/flox ;Hoxb7‐Cre (−) littermates as controls ( mVps34 Ctrl , Ctrl). By embryonic day 17.5, KO mice began to show dilated collecting ducts and proximal tubules, the earliest morphological alterations observed. At birth, KO mice exhibited markedly decreased kidney‐to‐body weight ratios (0.21±0.02% in KO vs. 0.42±0.18% in Ctrl; N =10, P <0.0001), with indistinguishable body weight. By 4 weeks of age, KO mice had a 48% reduction in glomerular number ( N =6, P <0.0008) and exhibited unproportionally thinner renal medulla, marked glomerular and tubular hypertrophy, glomerulosclerosis, interstitial fibrosis, proteinuria, and elevated BUN. By 12 weeks of age, KO mice developed hypertension (129.12±0.5 mmHg vs. Ctrl mice: 110.54±0.01; N =7, P <0.0001). TUNEL‐ and cleaved caspase 3‐positive cells were markedly increased, with decreased Akt phosphorylation. These data demonstrate an essential role for mVps34 in the renal collecting duct dictating nephron number and maintaining normal renal structure and function through a mechanism of antagonizing programmed cell death.