TY - JOUR
T1 - mVps34 deletion in podocytes causes glomerulosclerosis by disrupting intracellular vesicle trafficking
AU - Chen, Jianchun
AU - Chen, Mystie X.
AU - Fogo, Agnes B.
AU - Harris, Raymond C.
AU - Chen, Jian Kang
PY - 2013/1/31
Y1 - 2013/1/31
N2 - Recent studies have suggested that autophagy is a key mechanism in maintaining the integrity of podocytes. The mammalian homologue of yeast vacuolar protein sorting defective 34 (mVps34) has been implicated in the regulation of autophagy, but its role in podocytes is unknown. We generated a line of podocyte-specific mVps34-knockout (mVps34pdKO) mice, which were born at Mendelian ratios. These mice appeared grossly normal at 2 weeks of age but exhibited growth retardation and were significantly smaller than control mice by 6 weeks of age, with no difference in ratios of kidney to body weight. mVps34pdKO mice developed significant proteinuria by 3weeks of age, developed severe kidney lesions by 5-6weeks of age, and died before 9 weeks of age. There was striking podocyte vacuolization and proteinaceous casts, with marked glomerulosclerosis and interstitial fibrosis by 6 weeks of age. Electron microscopy revealed numerous enlarged vacuoles and increased autophagosomes in the podocytes, with complete foot process effacement and irregular and thickened glomerular basement membranes. Immunoblotting of isolated glomerular lysates revealed markedly elevated markers specific for lysosomes (LAMP1 and LAMP2) and autophagosomes (LC3-II/I). Immunofluorescence staining confirmed that the enlarged vacuoles originated from lysosomes. In conclusion, these results demonstrate an indispensable role for mVps34 in the trafficking of intracellular vesicles to protect the normal cellularmetabolism, structure, and function of podocytes.
AB - Recent studies have suggested that autophagy is a key mechanism in maintaining the integrity of podocytes. The mammalian homologue of yeast vacuolar protein sorting defective 34 (mVps34) has been implicated in the regulation of autophagy, but its role in podocytes is unknown. We generated a line of podocyte-specific mVps34-knockout (mVps34pdKO) mice, which were born at Mendelian ratios. These mice appeared grossly normal at 2 weeks of age but exhibited growth retardation and were significantly smaller than control mice by 6 weeks of age, with no difference in ratios of kidney to body weight. mVps34pdKO mice developed significant proteinuria by 3weeks of age, developed severe kidney lesions by 5-6weeks of age, and died before 9 weeks of age. There was striking podocyte vacuolization and proteinaceous casts, with marked glomerulosclerosis and interstitial fibrosis by 6 weeks of age. Electron microscopy revealed numerous enlarged vacuoles and increased autophagosomes in the podocytes, with complete foot process effacement and irregular and thickened glomerular basement membranes. Immunoblotting of isolated glomerular lysates revealed markedly elevated markers specific for lysosomes (LAMP1 and LAMP2) and autophagosomes (LC3-II/I). Immunofluorescence staining confirmed that the enlarged vacuoles originated from lysosomes. In conclusion, these results demonstrate an indispensable role for mVps34 in the trafficking of intracellular vesicles to protect the normal cellularmetabolism, structure, and function of podocytes.
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U2 - 10.1681/ASN.2012010101
DO - 10.1681/ASN.2012010101
M3 - Article
C2 - 23291473
AN - SCOPUS:84873380313
SN - 1046-6673
VL - 24
SP - 198
EP - 207
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 2
ER -