Transcription Factor Sp1 Expression Is Upregulated in Human Glomerulonephritis: Correlation with pSmad2/3 and p300 Expression and Renal Injury

Figures & data

Figure 1.  A schematic representation of the TGF-β-Smad signaling pathway (see text for details).

Table 1  Classification and clinical parameters of patients with glomerulonephritis

Disease	Number of patients	Age (years)	Gender (% male)	Serum creatinine (mg/dL)	24-hour urinary protein (g/d)
Non-proliferative primary GNs
MCD	10	39.5 ± 19.6	90	0.92 ± 0.12	5.7 ± 3.1
FSGS	16	36.5 ± 14.7	69	1.21 ± 0.58	3.3 ± 3.35
MGN	27	59.7 ± 16.1	67	1.24 ± 0.82	6.23 ± 6.2
Proliferative primary GNs
IgA	25	33.1 ± 13.4	73	0.92 ± 0.36	1.69 ± 1.64
MPGN	7	41.6 ± 28.2	14	1.65 ± 0.20	6.34 ± 5.3
PostIn GN	6	40.6 ± 25.1	84	3.95 ± 2.19	3.35 ± 0.91
Non-proliferative secondary GNs
NPLN	18	38.7 ± 11.1	17	1.33 ± 0.82	1.68 ± 2.15
Proliferative secondary GNs
PLN	25	34 ± 9.4	12	1.37 ± 0.71	3.27 ± 2.6
Pauci-Im GN	23	52.2 ± 19.6	52	3.69 ± 2.26	0.91 ± 0.97

Data are presented as mean ± 1 standard deviation. Note: to convert serum creatinine in mg/dL to μmol/L, multiply by 88.4.

Abbreviations: MCD = minimal change disease, FSGS = focal segmental glomerulosclerosis, MGN = membranous GN, IgA = IgA nephropathy, MPGN = membranoproliferative GN, PostIn = postinfectious GN, NPLN = nonproliferative lupus nephritis (SLE II/V), PLN = proliferative lupus nephritis (SLE III/IV), Pauci-Im GN = pauci-immune GN.

Figure 2.  Sp1 expression in normal human kidney. (a) About 40% of cells within the glomerulus were Sp1-positive, including podocytes, mesangial, endothelial, as well as parietal epithelial cells (arrows). (b) Proximal tubular cells (arrow) were either negative or weakly stained, while distal (arrowhead) and collecting tubules were constantly Sp1 positive. Original magnification ×400.

Figure 3.  Glomerular (a), proximal tubular (b), distal tubular (c) and collecting tubular (d) staining scores of Sp1 in normal and diseased human kidneys. The error bars represent SE. *p < 0.05, ^**p < 0.01, ^***p < 0.001. For abbreviations, see legend to Table 1.

Table 2  Comparison of Sp1 staining intensity in proliferative vs. nonproliferative GNs

	Staining score
	Sp1	p
Glomerulus
Proliferative	2.60 ± 0.59	0.123
Nonproliferative	2.35 ± 0.79
Proximal tubules
Proliferative	1.98 ± 0.57	0.025
Nonproliferative	1.75 ± 0.58
Distal tubules
Proliferative	3.00 ± 0.00	0.313
Nonproliferative	2.98 ± 0.13
Collecting tubules
Proliferative	2.54 ± 4.86	0.088
Nonproliferative	2.41 ± 0.49

Staining scores are presented as mean ± 1 standard deviation.

Table 3  Comparison of Sp1 staining intensity in secondary vs. primary proliferative GNs

Proliferative GNs		Staining score Sp1	p
Glomerulus
Secondary		2.77 ± 0.43	0.015
Primary		2.41 ± 0.63
Proximal tubules
Secondary		2.00 ± 0.58	0.815
Primary		1.97 ± 0.57
Distal tubules
Secondary		3.00 ± 0.00	1.000
Primary		3.00 ± 0.00
Collecting tubules
Secondary		2.74 ± 0.45	0.730
Primary		2.52 ± 0.51

Staining scores are presented as mean ± 1 standard deviation.

Figure 4.  Sp1 immunopositivity in various pathologic lesions of diseased glomeruli: a) hyperplastic lesions (proliferative lupus nephritis, WHO class IV), b) a cellular crescent (arrows) (Wegener granulomatosis), (c) a microadhesion (arrows) (proliferative lupus nephritis, WHO class IV), d) a globally sclerosed glomerulus, and e) a segmental sclerotic lesion (arrows) (IgA nephropathy); (e–g) serial sections of a glomerulus from a patient with IgA nephropathy exhibiting prominent Sp1 (4e), pSmad2/3 (4f) and p300 expression (4g) in cells overlying a sclerotic segment. (Figures 4e and 4g are reproduced from Kassimatis et al. [2006].^[17]) Original magnification ×400.

Table 4  The percentages of Sp1 immunopositivity incidence in the various lesions of the different groups of GN

	Glomeruli Total number of cases	Segmental hyperplasia	Cellular crescents	Micro-adhesions	Segmental sclerosis	Global sclerosis
Non-proliferative primary GNs	49			97%	83%	70%
Non-proliferative SLE GNs	18			100%
Proliferative primary GNs	37	100%	100%	89%	83%	89%
Proliferative secondary GNs	48	100%	100%	92%	83%	100%
All GNs	152	100%	100%	94%	83%	83%

Table 5  Correlation of Sp1 with pSmad2/3 and p300 expression at correspondent nephron sites

	Glomerulus	Proximal tubules	Distal tubules	Collecting tubules
	All/NP/P	All/NP/P	All/NP/P	All/NP/P
Sp1/pSmad2/3	0.175/−0.013/0.320	0.241/0.367/0.031	−/−/−	0.094/0.070/0.100
Sp1/p300	0.150/0.281/−0.050	0.244/0.321/0.060	−0.042/−0.064/−	0.025/0.118/−0.093

The Sp1 immunohistochemical staining score was correlated with pSmad2/3 and p300 staining scores at correspondent nephron sites using the Spearman single correlation coefficient. Sp1 expression in distal tubules of proliferative GN was constant.

*p < 0.05.

Abbreviations: All = all glomerulonephritides, NP = nonproliferative GN, P = proliferative GN.

Table 6  Correlations between immunohistochemical, clinical, and histologic parameters

	Scr (All/NP/P)	Prot (All/NP/P)	Glomscl (All/NP/P)	IF (All/NP/P)	TA (All/NP/P)	II (All/NP/P)
Sp1
Glomerulus	0.265/0.205/0.320	−0.160/-0.234/-0.018	−0.020/0.052/0.034	0.053/0.095/0.000	0.043/0.079/0.007	0.102/0.139/-0.003
Proximal tubules	0.306/0.271/0.270	0.021/0.000/0.082	0.042/0.097/-0.006	0.213/0.283*/0.102	0.139/0.249/0.003	0.122/0.209/-0.104
Distal tubules	0.087/0.104/-	-/-/-	−0.086/-0.123/-	−0.101/-0.147/-	−0.139/-0.184/-	−0.021/-0.100/-
Collecting tubules	0.181/0.220/0.080	−0.209/-0.208/-0.191	−0.007/-0.022/0.038	−0.016/-0.168/0.088	−0.013/-0.076/0.047	0.082/0.165/-0.146

The immunohistochemical staining score at various nephron sites was compared with clinical data (serum creatinine levels and 24-hour urinary protein) and indices of histologic injury, using the Spearman single correlation coefficient in all glomerulonephritides (All), nonproliferative GN (NP), and proliferative GN (P). Values are given as r; Sp1 expression in distal tubules of proliferative GN was constant.

*p < 0.05.

Abbreviations: Scr = serum creatinine, Prot = 24-hour urinary protein, glomscl = glomerulosclerosis, IF = interstitial fibrosis, TA = tubular atrophy, II = interstitial inflammation.

Kassimatis TI, Giannopoulou I, Koumoundourou D, Theodorakopoulou E, Varakis I, Nakopoulou L. Immunohistochemical evaluation of phosphorylated SMAD2/SMAD3 and the co-activator P300 in human glomerulonephritis: Correlation with renal injury. J Cell Mol Med. 2006;10:908–921.

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