Submitted on March 24, 2005
Accepted on June 20, 2005
Disruption of Glomerular Cell-Cell an Cell-Matrix Interactions in Hydrocarbon Nephropathy
Adrian Nanez1, Napoleon F Alejandro2, M Hadi Falahatpisheh1, J. Kevin Kerzee2, John B Roths3, and Kenneth S Ramos4*
1 Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, TX, USA
2 Department of Physiology and Pharmacology, Texas A&M University, College Station, TX, USA
3 Department of Pathobiology, Texas A&M University, College Station, TX, USA
4 Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, TX, USA; Department of Physiology and Pharmacology, Texas A&M University, College Station, TX, USA
* To whom correspondence should be addressed. E-mail: kenneth.ramos{at}louisville.edu.
Environmental chemicals play an etiological role in greater than 50% of
idiopathic glomerular diseases. The present studies were conducted to define
mechanisms of renal cell-specific hydrocarbon injury. Female rats were given 10 mg/kg
benzo(a)pyrene (BaP) once a week for 16 weeks. Progressive elevations in total urinary
protein, protein/creatinine ratios and microalbuminuria were observed in rats treated with
BaP for up to 16 weeks. The nephropathic response involved early reductions in
mesangial cell numbers and fibronectin levels by 8 weeks, coupled to transient increases
in podocyte cellularity. Changes in podocyte numbers subsided by 16 weeks and
correlated with rebound increases in mesangial cell numbers and fibronectin levels, along
with increased 
-smooth muscle actin and Cu/Zn superoxide dismutase, and fusion of
podocyte foot processes. In culture, mesangial cells were more sensitive than podocytes
to hydrocarbon injury and expressed higher levels of inducible aryl hydrocarbon
hydroxylase activity. Naive mesangial cells exerted a strong inhibitory influence on
podocyte proliferation under both direct and indirect co-culture conditions, and this
response involved a mesangial cell-derived matrix that selectively inhibited podocyte
proliferation. These findings indicate that hydrocarbon nephropathy in rats involves
disruption of glomerular cell-cell and cell-matrix interactions mediated by deposition of a
mesangial cell-derived growth inhibitory matrix that regulates podocyte proliferation.
