Hyperlipidemia aggravates renal disease in B6.ROP Os/+ mice.
BACKGROUND
Reduction of renal mass is frequently associated with progressive loss of kidney function. We examined the effects of hyperlipidemia on renal pathology and mediators of tissue damage in B6.ROP Os/+ mice, a model of reduced renal mass.


METHODS
C57BL/6 control mice and B6.ROP Os/+ mice were fed normal rodent chow or a high fat, high cholesterol (HFHC) diet for 12 weeks. Kidney function and renal pathology were assessed.


RESULTS
Hyperlipidemia led to a decline in kidney function in C57BL/6 mice. Renal pathology was characterized by an increase in glomerular matrix and cellularity, glomerular and tubulointerstitial macrophage influx, and increased tubular epithelial cell turnover. Chow-fed B6.ROP Os/+ animals demonstrated glomerular hypertrophy with an increase in mesangial matrix and cellularity that was characterized by macrophage influx and increased proliferation. The tubulointerstitium showed increased macrophages as well as tubular atrophy and dilation. Renal pathology was accompanied by an increase in blood urea nitrogen (BUN) and proteinuria. Hyperlipidemia in B6.ROP Os/+ mice resulted in increased plasma BUN compared to chow-fed B6.ROP Os/+ animals and aggravated renal pathology by further increasing glomerular matrix and glomerular hypercellularity. Glomerular hypercellularity was associated with increased expression of platelet-derived growth factor-B (PDGF B) and its receptor beta. Glomerular transforming growth factor-beta (TGF-beta) mRNA expression was increased in B6.ROP Os/+ mice, hyperlipidemic C57BL/6 mice and hyperlipidemic B6.ROP Os/+ animals compared to controls and correlated with the amount of mesangial matrix.


CONCLUSIONS
This study demonstrates that hyperlipidemia worsens renal pathology in B6.ROP Os/+ mice with a decline in renal function mediated at least in part through increased renal expression of the cytokines PDGF B and TGF-beta.
Department of Pathology, University of Washington, Seattle, Washington 98195, USA.
Anja S
AS
Mühlfeld
Min W
MW
Spencer
Kelly L
KL
Hudkins
Elizabeth
E
Kirk
Renee C
RC
LeBoeuf
Charles E
CE
Alpers
D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics; D005109:Extracellular Matrix / Q000473:pathology; D005260:Female; D005920:Glomerular Mesangium / Q000473:pathology* / Q000503:physiopathology / Q000648:ultrastructure; D006943:Hyperglycemia; D006949:Hyperlipidemias / Q000150:complications* / Q000503:physiopathology; D006984:Hypertrophy; D007333:Insulin Resistance; D007674:Kidney Diseases / Q000209:etiology* / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D009765:Obesity; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000235:genetics
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta