Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model

Abstract

Increasing evidence supports a role of glomerular cell proliferation in the development of focal or diffuse glomerulosclerosis. This study investigates the chronology and sequence of cellular events that precede glomerulosclerosis in 5/6 nephrectomized rats. Within three days of renal ablation, a phenotypic switch occurred in which some mesangial cells expressed alpha-smooth muscle actin. This was followed by proliferation of mesangial cells, and to a lesser degree endothelial cells from day 5 to week 4 as detected by immunostaining for the proliferating cell nuclear antigen (PCNA). Glomerular cell proliferation was accompanied by increased immunohistochemical expression of PDGF B-chain. In situ hybridization showed no glomerular PDGF B-chain mRNA expression at the induction of proliferation (day 5), and a marked increase between week 1 and 4 in operated rats. In parallel, increased expression of PDGF receptor beta-subunit protein and mRNA was demonstrated by immunohistochemistry and Northern analysis of total glomerular RNA. The onset of glomerular cell proliferation was also associated with mild glomerular platelet accumulation (as defined by 111In-labelled platelet studies) as well as with fibrinogen deposition. Proteinuria, glomerular sclerotic changes, and leukocyte infiltration all followed cell proliferation. The glomerular leukocyte infiltrate consisted of monocytes/macrophages and increased markedly at week 10 in rats with renal ablation. Thus, our results suggest that in the remnant kidney model: 1) proliferation of intrinsic glomerular cells precedes glomerulosclerosis; 2) proliferation may be initiated by degranulating platelets and sustained by PDGF released from intrinsic glomerular cells; and 3) glomerular monocyte/macrophage infiltration occurs after the proliferation, and may possibly contribute to the development of glomerular sclerotic changes.

Inhibitory effects of adiponectin on platelet-derived growth factor-induced mesangial cell migration

“…05 versus PDGF 10 ng/ml without adiponectin). demonstrating increased MC proliferation and glomerular PDGF expression in the five out of six nephrectomized rats, which were well-established models of CKD (Floege et al 1992). These findings suggest that PDGF-induced RMC disorders in the glomeruli may contribute to glomerular injury leading to CKD.…”

Comparison of tumour necrosis factor and endothelin-1 between essential and renal hypertensive patients

“…2,22,23 Several studies have shown that both platelet-derived and transforming growth factors, as well as TNF␣ may play a role in the pathogenesis of glomerular injury. 6,7,24,25 TNF␣ enhances the expression of intercellular adhesion molecule-1 (ICAM-1) 9 and blood levels of ICAM-1 were found to be increased in atherosclerotic hypertensive subjects with preserved renal function, suggesting a systemic endothelial dysfunction. 26 Furthermore, on the basis of experimental results Liu et al 27,28 hypothesised that in hypertension, vascular thrombotic risk is associated with Table 1 Mean age, serum creatinine and creatinine clearance (Clcr), blood levels of TNF␣ and ET-1, UAE, 24-h systolic-(SBP), diastolic (DBP) and mean (MBP) blood pressures in normotensive controls (NT), in patients with essential hypertension (EH), and in hypertensive subjects with renal insufficiency (CRF)…”

The involvement of activated T cells and growth-factor production in the early and late phase of chronic kidney allograft nephropathy in rats

“…In treated and untreated animals, PDGF synthesis increased from weeks 16 to 24, despite considerable reduction of infiltrating cells. Since PDGF is produced not only by platelets, but by mesangial cells as well [12], it is suggested that glomerular cell proliferation may become self-perpetuating by an autocrine mechanism involving mesangial cell production of PDGF [12]. Therefore, PDGF may be more important for the later progression of CAN than TGF-P1.…”