Heparin suppresses mesangial cell proliferation and matrix expansion in experimental mesangioproliferative glomerulonephritis

Heparin suppresses mesangial cell proliferation and matrix expansion in experimental mesangioproliferative glomerulonephritis. Proliferation and extracellular matrix (ECM) overproduction by glomerular mesangial cells characterizes many types of glomerulonephritis and often precedes the development of glomerulosclerosis. Heparin is a potent inhibitor of mesangial cell growth in vitro. We examined whether standard heparin can inhibit mesangial cell proliferation in vivo in the mesangioproliferative anti-Thy 1.1 nephritis. Untreated control rats were compared to rats infused with heparin either early (day -2 to 1) or late (day 2 to 5) after induction of anti-Thy 1.1 nephritis. The results show that heparin treatment significantly reduced mesangial cell proliferation regardless of when it was initiated. Heparin (either early or late treatment) also reduced mesangial basic fibroblast growth factor (bFGF) expression and platelet-derived growth factor (PDGF) receptor up-regulation as reflected by immunostaining, whereas PDGF B-chain expression was reduced only by late heparin treatment. Furthermore, heparin treatment markedly inhibited the mesangial matrix expansion for a variety of ECM proteins, including laminin, type I and IV collagen, fibronectin and entactin. Heparin did not affect the initial mesangiolysis, glomerular macrophage influx, deposition of anti-Thy 1.1 IgG or fibrinogen, or the glomerular platelet influx. These results suggest that heparin, via its antiproliferative rather than anticoagulant effect, can inhibit mesangial cell proliferation, overexpression of polypeptide growth factors, and ECM protein overproduction in vivo. The beneficial effect of heparin can be demonstrated even if treatment is initiated after the development of nephritis. By virtue of these properties, heparin may be an effective agent in the treatment of human mesangioproliferative disease and in the prevention of glomerulosclerosis

Renal Proliferative and Phenotypic Changes in Rats With Two-Kidney, One-Clip Goldblatt Hypertension

Angiotensin II (All) is a vasoconstrictive peptide with hypertrophic and mitogenic effects on many cell types. Previous studies have shown that in vivo administration of All in rats results in proliferation of, and phenotypic changes in, many renal cell populations, but in doses also causing hypertension. Thus, it was not possible to differentiate nonhemodynamic from hypertensive effects of All. Therefore, we studied rats with renin-dependent, All-mediated hypertension (the two-kidney, oneclip Goldblatt model; mean systolic blood pressure 238 ± 48 ν 140 ± 6 mm Hg in sham-operated controls). The undipped kidneys, which were exposed to high blood pressure, developed significant glomerular and tubulointerstitial injury, tubulointerstitial cell proliferation, dense focal interstitial monocyte-macrophage influx, increased deposition of types I and IV collagen, as well as increased cellular expression of desmin and actin, in tubulointerstitial areas when examined at 11 weeks. In contrast, clipped kidneys, protected from hypertension but with high local renin expression, had minimal abnormalities. These studies suggest that in this model increased renin, and presumably All, does not mediate significant proliferative or phenotypic changes in the kidney in the absence of hypertension at 11 weeks. Am J Hypertens 1994;7:177-18

Modulation of experimental mesangial proliferative nephritis by interferon-γ

Modulation of experimental mesangial proliferative nephritis by interferon-γ. The observation that interferon-γ (IFN-γ) inhibits cell proliferation and collagen synthesis of a variety of cell types in culture has suggested that IFN-γ may be useful in the treatment of fibroproliferative diseases. We administered recombinant IFN-γ subcutaneously (105 U/kg/day for 3 days) to rats, beginning one day after the induction of mesangial proliferative nephritis with anti-Thy 1 antibody. IFN-γ reduced glomerular (primarily mesangial) cell proliferation by 44% at days 2 and 4 compared to vehicle injected control rats with anti-Thy 1 nephritis (that is, proliferating cells that excluded the macrophage marker, ED-1, P < 0.001). Despite the inhibition of mesangial cell proliferation, IFN-γ did not reduce the overall extracellular matrix deposition (by silver stain) or deposition of type IV collagen or laminin (by immunostaining) at 4 or 7 days, and glomerular type IV collagen and laminin mRNA levels were increased (1.4 and 1.7-fold) at 4 days relative to controls. The inability of IFN-γ treatment to reduce mesangial matrix expansion may relate to the fact that IFN-γ treated rats had a twofold increase in glomerular macrophages (that is, ED-1 positive cells, P < 0.001 at 2 and 4 days) with an increase in oxidant producing cells (day 2, P < 0.05) and a 1.6-fold increase in glomerular TGF-β mRNA expression (4 days). This suggests that the effect of IFN-γ to inhibit mesangial cell proliferation in glomerulonephritis may be offset by the ability of IFN-γ to increase glomerular macrophages and TGF-β expression. These data also show that IFN-γ can partly dissociate the mesangial proliferative response from the extracellular matrix expansion in glomerulonephritis

Whole-Genome Sequencing of Finnish Type 1 Diabetic Siblings Discordant for Kidney Disease Reveals DNA Variants associated with Diabetic Nephropathy

Background Several genetic susceptibility loci associated with diabetic nephropathy have been documented, but no causative variants implying novel pathogenetic mechanisms have been elucidated. Methods We carried out whole-genome sequencing of a discovery cohort of Finnish siblings with type 1 diabetes who were discordant for the presence (case) or absence (control) of diabetic nephropathy. Controls had diabetes without complications for 15-37 years. We analyzed and annotated variants at genome, gene, and single-nucleotide variant levels. We then replicated the associated variants, genes, and regions in a replication cohort from the Finnish Diabetic Nephropathy study that included 3531 unrelated Finns with type 1 diabetes. Results We observed protein-altering variants and an enrichment of variants in regions associated with the presence or absence of diabetic nephropathy. The replication cohort confirmed variants in both regulatory and protein-coding regions. We also observed that diabetic nephropathy-associated variants, when clustered at the gene level, are enriched in a core protein-interaction network representing proteins essential for podocyte function. These genes include protein kinases (protein kinase C isoforms epsilon and iota and protein tyrosine kinase 2. Conclusions Our comprehensive analysis of a diabetic nephropathy cohort of siblings with type 1 diabetes who were discordant for kidney disease points to variants and genes that are potentially causative or protective for diabetic nephropathy. This includes variants in two isoforms of the protein kinase C family not previously linked to diabetic nephropathy, adding support to previous hypotheses that the protein kinase C family members play a role in diabetic nephropathy and might be attractive therapeutic targets.Peer reviewe