Faculty Profiles - KAWACHI Hiroshi

Expression of podocyte-associated molecules in acquired human kidney diseases Reviewed

K Koop, M Eikmans, HJ Baelde, H Kawachi, E De Heer, LC Paul, JA Bruijn

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 14 ( 8 ) 2063 - 2071 2003.8

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Proteinuria is a poorly understood feature of many acquired renal diseases. Recent studies concerning congenital nephrotic syndromes and findings in genetically modified mice have demonstrated that podocyte molecules make a pivotal contribution to the maintenance of the selective filtration barrier of the normal glomerulus. However, it is unclear what role podocyte molecules play in proteinuria of acquired renal diseases. This study investigated the mRNA and protein expression of several podocyte-associated molecules in acquired renal diseases. Forty-eight patients with various renal diseases were studied. including minimal change nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, lupus nephritis, and diabetic nephropathy, together with 13 kidneys with normal glomerular function. Protein levels of nephrin, podocin, CD2-associated protein, and podocalyxin were investigated using quantitative immunohistochemical assays. Real-time PCR was used to determine the mRNA levels of nephrin, podocin, and podoplanin in microdissected glorneruli. The obtained molecular data were related to electron microscopic ultrastructural changes, in particular foot process width, and to clinical parameters. In most acquired renal diseases, except in IgA nephropathy, a marked reduction was observed at the protein levels of nephrin, podocin, and podocalyxin, whereas an increase of the glomerular mRNA levels of nephrin, podocin, and podoplanin was found, compared with controls. The mean width of the podocyte foot processes was inversely correlated with the protein levels of nephrin (r = -0.443, P < 0.05), whereas it was positively correlated with podoplanin mRNA levels (r = 0.468, P < 0.05) and proteinuria (r = 0.585, P = 0.001). In the diseases studied, the decrease of slit diaphragm proteins was related to the effacement of foot processes and coincided with a rise of the levels of the corresponding mRNA transcripts. This suggests that the alterations in the expression of podocyte-associated molecules represent a compensatory reaction of the podocyte that results from damage associated with proteinuria.

DOI： 10.1097/01.ASN.0000078803.53165.C9

Retinoids regulate the repairing process of the podocytes in puromycin aminonucleoside-induced nephrotic rats Reviewed

A Suzuki, T Ito, E Imai, M Yamato, H Iwatani, H Kawachi, M Hori

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 14 ( 4 ) 981 - 991 2003.4

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

The foot processes forming the slit diaphragm are disrupted in diseases associated with proteinuria. Although they are often repairable, regulators for the repairing process remain unknown. By extrapolating from the fact that vitamin A is essential for the nephrogenesis, this study examined whether or not injured podocytes in the middle of the repairing process require retinaldehyde dehydrogenase type 2 (RALDH2), one of the key enzymes to produce all-trans-retinoic acid (ATRA). RALDH2 was dramatically upregulated in podocytes of puromycin aminonucleoside-induced nephrosis (PAN nephrosis) rats. On day 5 of PAN nephrosis, RALDH2 showed the remarkable induction, whereas glomerular expression levels of nephrin and midkine, one of the ATRA target genes, were downregulated. Daily administration of ATRA ameliorated proteinuria, which was accompanied by the improvement in the effacement of the foot processes and by the induction of nephrin and midkine. In contrast, recovery from PAN nephrosis was delayed in rats fed with a vitamin A-deficient diet. Consistently, the promoter region of human nephrin gene (NPHS1) contained three putative retinoic acid response elements (RARE) and showed the enhancer activity in response to ATRA in a dose-dependent manner. This transcriptional activation was regulated through the receptors for retinoids because BMS-189453, an antagonist to the retinoid receptors, counteracted it in a dose-dependent manner. In conclusion, active metabolites of vitamin A, especially ATRA produced by RALDH2 play relevant roles during the repairing process of injured podocytes. The results obtained from PAN nephrosis rats might be applicable to human renal diseases.

DOI： 10.1097/01.ASN.0000057857.66268.8F

Disparate effects of angiotensin II antagonists and calcium channel blockers on albuminuria in experimental diabetes and hypertension: Potential role of nephrin Reviewed

Belinda J. Davis, Zemin Cao, Marc De Gasparo, Hiroshi Kawachi, Mark E. Cooper, Terri J. Allen

Journal of Hypertension 21 ( 1 ) 209 - 216 2003.1

Language：English Publishing type：Research paper (scientific journal)

Objective and design: To explore the effects of various antihypertensive regimes which achieve similar blood pressure control using a range of agents including the angiotensin II type 1 receptor antagonist, valsartan, as monotherapy or in combination with two subclasses of calcium channel blockers (CCBs) (the dihydropyridine, amlodipine and the phenylalkylamine, verapamil) on the progression of renal disease and the expression of the podocyte slit pore protein, nephrin in an accelerated model of diabetic nephropathy. Results: Valsartan treatment reduced systolic blood pressure as assessed by radiotelemetry (135 ± 3 versus diabetic 153 ± 6 mmHg) as well as retarding the increase in albumin excretion rate by approximately 50%. Combination therapy of valsartan with either amlodipine or verapamil was equally effective in reducing blood pressure to valsartan monotherapy (valsartan + amlodipine 129 ± 4 valsartan + verapami1133 ± 6 mmHg
) but was not as effective at reducing albuminuria. A reduction in glomerulosclerosis was observed with valsartan monotherapy with less reduction in injury with the valsartan + amlodipine combination, despite a similar reduction in blood pressure. The decrease in nephrin, in diabetic rats was attenuated by valsartan monotherapy, but not by other treatments. Conclusions: The results of this study demonstrate that despite a similar reduction in blood pressure, the addition of the CCB amlodipine to the All antagonist failed to provide similar renoprotection to that observed with an equihypotensive regimen of valsartan as monotherapy. Furthermore, the depletion in glomerular nephrin expression in diabetic animals was only abrogated by valsartan treatment, the therapy which was most effective at retarding the development of albuminuria in this model. © 2003 Lippincott Williams &amp
Wilkins.

DOI： 10.1097/00004872-200301000-00031

Cloning of rat homologue of podocin: Expression in proteinuric states and in developing glomeruli Reviewed

H Kawachi, H Koike, H Kurihara, T Sakai, F Shimizu

JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY 14 ( 1 ) 46 - 56 2003.1

Language：English Publishing type：Research paper (scientific journal) Publisher：LIPPINCOTT WILLIAMS & WILKINS

Podocin is identified as a product of the gene mutated in a patient with autosomal recessive steroid-resistant nephrotic syndrome. Although podocin is reported to be located at the slit diaphragm area, the precise role of podocin for maintaining the barrier function of the slit diaphragm has not been clearly elucidated. A rat homologue of podocin was cloned, and the expression of podocin was investigated and then compared with the nephrin and the ZO-1 expressions in rat experimental proteinuric models and in developing glomeruli. Amino acid sequences of rat and human podocin are highly homologous (84.3% identity). The domain structure of podocin is also highly conserved between rat and human. The mRNA expression for podocin was detected in glomeruli and the nerve tissues. The localization of podocin has close proximity to that of nephrin in normal adult rat glomeruli. Podocin staining was restricted to the basal side of the podocyte of the early developing stage, whereas nephrin staining was detected on the basolateral surface of podocyte. The redistribution of podocin was observed in the anti-nephrin antibody (ANA)-induced nephropathy and puromycin aminonucleoside (PAN) nephropathy. The redistribution of podocin paralleled with nephrin in ANA nephropathy but not in PAN nephropathy. Podocin is observed at the site of tight junction newly formed in proteinuric state in PAN nephropathy. It is postulated that podocin is one of the critical components of a slit diaphragm for maintaining the barrier function of the glomerular capillary wall. kawachi@med.niigata-u.ac.jl.

DOI： 10.1097/01.ASN.0000037401.02391.76

抗体による蛋白尿. Invited

河内裕

腎と透析 53 569 - 573 2002.12

糸球体バリアの構造と機能蛋白尿のメカニズム. Invited

清水不二雄, 河内裕

Medical Practice(文光堂) 19 448 - 449 2002.12

遺伝子異常と蛋白尿. Invited

河内裕

小児科 43 617 - 623 2002.12

Therapeutic effect of sulphated hyaluronic acid, a potential selectin-blocking agent, on experimental progressive mesangial proliferative glomerulonephritis Reviewed

Mitsuhiro Matsuda, Kenichi Shikata, Fujio Shimizu, Yasuo Suzuki, Masayuki Miyasaka, Hiroshi Kawachi, Hiroto Kawashima, Jun Wada, Hikaru Sugimoto, Yasushi Shikata, Daisuke Ogawa, Shinichiro J. Tojo, Kazuo Akima, Hirofumi Makino

Journal of Pathology 198 ( 3 ) 407 - 414 2002.11

Language：English Publishing type：Research paper (scientific journal)

The initial event in the process of leukocyte infiltration is characterized by leukocyte rolling on the surface of the endothelium, which is mediated by selectins. P- and L-selectin bind to the sulphated sugar chains of their natural ligands, including sulphated glycolipids such as sulphatide. Recently, it has been demonstrated that sulphated glycolipids and sulphated oligosaccharides interfere with selectin binding pathways. This study synthesized sulphated hyaluronic acid (SHA), which is a potential selectin-blocking agent, and examined its therapeutic effect on the experimental progressive mesangial proliferative glomerulonephritis induced by anti-Thy-1 monoclonal antibody (1-22-3 MAb) after unilateral nephrectomy. The selectin-inhibitory effect of SHA in vitro was confirmed. SHA inhibited the binding of P- and L-selectin to sulphatide, which is a glycolipid ligand for P- and L-selectin, at a concentration of 1.5 μg/ml and 100 μg/ml. Immunohistochemical examination showed that P-selectin was up-regulated in the glomeruli in the 1-22-3 MAb nephritis model, while the ligands for L-selectin were not detected in the glomerular tufts. A single administration of SHA ameliorated proteinuria and glomerular leukocyte infiltration in 24 h after the injection of anti-Thy-1 MAb. Anti-P-selectin MAb, but not anti-L-selectin MAb, inhibited proteinuria and glomerular leukocyte infiltration. To examine further the therapeutic effect of SHA on chronic glomerulonephritis, SHA was administered daily from day 3 to day 14 in this model. Proteinuria and glomerular leukocyte infiltration were significantly diminished in SHA-treated rats on day 14. These results suggest that SHA ameliorated rat progressive mesangial proliferative glomerulonephritis by inhibiting P-selectin-dependent leukocyte infiltration in glomeruli. Sulphated oligosaccharides may be beneficial for the therapy of mesangial proliferative glomerulonephritis. Copyright © 2002 John Wiley &amp
Sons, Ltd.

DOI： 10.1002/path.1209

Fractalkine expression and the recruitment of CX(3)CR1(+) cells in the prolonged mesangial proliferative glomerulonephritis Reviewed

Y Ito, H Kawachi, Y Morioka, T Nakatsue, H Koike, Y Ikezumi, A Oyanagi, Y Natori, Y Natori, T Nakamura, F Gejyo, F Shimizu

KIDNEY INTERNATIONAL 61 ( 6 ) 2044 - 2057 2002.6

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING INC

Background. We established the reversible and the prolonged models of mesangial proliferative glomerulonephritis (GN) with anti-Thy 1 antibody 1-22-3. However, the essential factors leading to the prolonged glomerular alterations have not been identified.
Methods. The expressions of several chemokines and cytokines were compared in the reversible and the prolonged models. Expression of fractalkine and the number of the fractalkine receptor CX3 CR1-positive cells in the glomeruli in the prolonged model were significantly higher than those in the reversible model. Then, the localization of fractalkine and the characteristics of CX3 CR1(+) cells were analyzed in glomeruli. To elucidate the significance of the fractalkine expression, we analyzed the expression in the model treated with angiotensin II receptor antagonist, candesartan.
Results. Immunostaining of fractalkine was detected on endothelial cells on the fifth day, and fractalkine staining also was detected in the mesangial area on day 14. Major parts of the CX3 CR1(+) cells in the glomeruli were macrophages, especially ED3(+) cells. Candesartan treatment ameliorated the glomerular morphological findings at six weeks after disease induction. Although the treatment did not ameliorate the morphological finding at two weeks, decreased expression of fractalkine and CX3 CR1(+) were already detected at two weeks in rats treated with candesartan.
Conclusions. Fractalkine expression and the recruitment of CX3 CR1(+) cells in glomeruli might play an important role in the development of the prolonged disease. These expressions could be predictors of the prolonged disease of the mesangial proliferative glomerulonephritis.

mAb 5-1-6 nephropathy and nephrin Invited Reviewed

H Kawachi, H Koike, F Shimizu

MICROSCOPY RESEARCH AND TECHNIQUE 57 ( 4 ) 236 - 240 2002.5

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-LISS

It is well established that the glomerular capillary wall consists of three layers: endothelial cell, glomerular basement membrane, and the slit diaphragm bridging foot processes of glomerular epithelial cell. Which structure in the glomerular capillary wall represents the primary filter for retaining plasma proteins is not clearly elucidated. An anti-slit diaphragm monoclonal antibody (mAb) 5-1-6 causes massive proteinuria in rats by single intravenous injection, which clearly indicates that the slit diaphragm plays a critical role for maintaining the barrier function of the glomerular capillary wall. Recently, we concluded that mAb 5-1-6 recognized a rat homolog of nephrin, a gene product of NPHS1. The expression of nephrin decreased in puromycin aminonucleoside nephropathy and adriamycin nephropathy as well as mAb 5-1-6-induced nephropathy, which suggested that nephrin was involved in the development of proteinuria in these proteinuric states, In mAb 5-1-6 nephropathy, the slit diaphragm was maintained morphologically normal, although nephrin expression dramatically decreased. The finding suggested that nephrin was not a sole component of the slit diaphragm. To better understand the structure of the slit diaphragm, it is particularly important to identify other components that build up the structure of the slit diaphragm together with nephrin. (C) 2002 Wiley-Liss, Inc.

DOI： 10.1002/jemt.10081

Kidney-targeted naked DNA transfer by retrograde renal vein injection in rats Reviewed

Hiroki Maruyama, Noboru Higuchi, Yuji Nishikawa, Hiroyuki Hirahara, Noriaki Iino, Shigemi Kameda, Hiroshi Kawachi, Eishin Yaoita, Fumitake Gejyo, Jun-Ichi Miyazaki

Human Gene Therapy 13 ( 3 ) 455 - 468 2002.2

Language：English Publishing type：Research paper (scientific journal)

Kidney-targeted gene transfer is expected to revolutionize the treatment of renal diseases. Previous gene transfer methods using nonviral vectors administered via renal arterial, pelvic, or ureteric routes into the glomerulus, tubules, or interstitial fibroblasts have resulted in low-level expression for &lt
1 month. The peritubular capillaries (PTC) network is one of the main targets of kidney transplant rejection and of progressive tubulointerstitial fibrosis, which typifies all progressive renal diseases. To access the PTC, we retrogradely injected a lacZ expression plasmid in Ringer's solution into the renal vein of rats. We detected lacZ expression exclusively in the interstitial fibroblasts near the PTC of the injected kidney by immunoelectron microscopic analysis. Nephrotoxicity attributable to gene transfer was not apparent. We then used a rat erythropoietin (Epo) expression plasmid vector, pCAGGS-Epo, in a reporter assay. We obtained maximal Epo expression when the DNA solution was injected within 5 sec, and with a volume of 1.0 ml. We observed a dose-response relationship between serum Epo levels and the amount of injected DNA up to 100 μg. We detected the transgene-derived Epo mRNA by reverse transcription polymerase chain reaction only in the kidneys injected with pCAGGS-Epo. After an injection of 100 μg of pCAGGS-Epo, the serum Epo levels peaked at 208.3 ± 71.8 mU/ml at week 5, and gradually decreased to 116.2 ± 38.7 mU/ml at week 24. A similar pattern was obtained using smaller doses of plasmid, 2 μg or 30 μg of pCAGGS-Epo. Transgene-derived Epo secretion resulted in significant erythropoiesis. This novel technique is simple and safe, allowing high-level and long-term stable gene expression specific to the fibroblasts near the PTC, and should have therapeutic value for future applications in humans.

DOI： 10.1089/10430340252792585

Rapidly progressive, pauci-immune diffuse crescentic glomerulonephritis in an infant Reviewed

Hiroshi Tanaka, Shinobu Waga, Koichi Suzuki, Tohru Nakahata, Hiroshi Kawachi, Fujio Shimizu, Etsuro Ito

Pediatric Nephrology 17 ( 9 ) 730 - 732 2002

Language：English Publishing type：Research paper (scientific journal)

A Japanese male infant presented with nephrotic syndrome at 41 days. His renal function progressively deteriorated, and he died at 4 months of the age. An open renal biopsy revealed diffuse crescentic glomerulonephritis (CrGN) without immune complex deposition, which is not characteristic of the congenital nephrotic syndrome (CNS). Examination for nephrin antigen using rabbit anti-nephrin extra- and intracellular site antibodies was positive. These clinical observations suggest that the patient had a unique histological variant of CNS. This is the first report of rapidly progressive, pauci-immune diffuse CrGN in infancy.

DOI： 10.1007/s00467-002-0938-7

Molecular structure and function of the slit diaphragm: expression of nephrin in proteinuric states and in developing glomeruli Invited Reviewed

H Kawachi, H Koike, F Shimizu

NEPHROLOGY DIALYSIS TRANSPLANTATION 17 ( 9 ) 20 - 22 2002

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Nephrin is identified as a product of the gene mutated in a patient with congenital nephrotic syndrome of the Finnish type. To analyse the function of nephrin and the relationship of nephrin and the target antigen of nephritogenic anti-rat slit diaphragm monoclonal antibody (mAb) 5-1-6, the rat homologue of nephrin was cloned. The deduced amino acid sequence of rat nephrin shows 82.2% homology to human nephrin. Signal sequences of rat nephrin are 36 amino acids, whereas those of human nephrin are reported to be 22 amino acids. The localization of rat nephrin always coincided with that of mAb 5-1-6 antigen. The specific anti-nephrin antibody recognized the mAb 5-1-6-antigen complex. mAb 5-1-6 reacted with COS cells transfected with rat nephrin cDNA. These results demonstrate that nephritogenic mAb 5-1-6 identifies the extracellular domain of rat nephrin, thereby documenting that nephrin is a functional protein of the slit diaphragm. The staining pattern of nephrin shifted from a linear-like pattern to a discontinuous coarse granular pattern not only in mAb 5-1-6-induced nephropathy, but also in puromycin aminonucleoside nephropathy, adriamycin nephropathy and passive Heymann nephropathy. Rat nephrin is detected first on the basal and lateral side below the junctional complex at the S-shaped body stage. With the interdigitation of foot processes, nephrin becomes concentrated in the slit pore, and finally restricted in the site of the slit diaphragm bridging two adjacent foot processes.

FK506 ameliorates proteinuria and glomerular lesions induced by anti-Thy 1.1 monoclonal antibody 1-22-3 Reviewed

Yohei Ikezumi, Katsue Kanno, Hiroko Koike, Masayuki Tomita, Makoto Uchiyama, Fujio Shimizu, Hiroshi Kawachi

Kidney International 61 ( 4 ) 1339 - 1350 2002

Language：English Publishing type：Research paper (scientific journal) Publisher：Blackwell Publishing Inc.

Background. We have previously reported that CD4 T lymphocytes and their cytokines contribute to development of Thy 1.1 glomerulonephritis (GN). FK506 is reported to suppress the production of Th1 cytokines. The aims of this study were to elucidate the role of Th1 cytokines on mesangial alteration and to examine whether FK506 is available for therapy of mesangial proliferative GN. Methods. The effects of daily treatments of FK506 from day -5 and from day +1 of Thy 1.1 GN induction on glomerular alterations were analyzed. Results. FK506 treatment with 1.0 and 0.3 mg/kg body weight (BW) daily from day 1 to day 4 significantly reduced the glomerular expression of mRNA for interferon-γ (IFN-γ 1.0 mg/kg BW FK506, 32.4% to the placebo group, P &lt
0.01) and IL-2 (55.6%, P &lt
0.01) on day 5. FK506 treatment from day -5 of GN induction reduced proteinuria and glomerular alteration in a dose-dependent manner. Although no side effects were detected in rats with 0.3 mg/kg BW of FK506 treatment from day +1, the treatment also ameliorated proteinuria (day 14, 3.7 ± 0.89 vs. 19.8 ± 12.3 mg/100 g BW/day P &lt
0.05) and glomerular alterations [total cell number, 63.1 ± 3.1 vs. 80.2 ± 7.4, P &lt
0.01
matrix expansion, 0.90 ± 0.30 vs. 1.34 ± 0.27, P &lt
0.05
α-smooth muscle actin (αSMA) expression
1.20 ± 0.12 vs. 1.96 ± 0.29, P &lt
0.01] on day 14. Conclusion. Th1 cytokines may play an important role in the development of mesangial proliferative glomerulonephritis, and could be targets for therapy. FK506 might be available for clinical use.

DOI： 10.1046/j.1523-1755.2002.00259.x

Nephrin expression in the post-natal developing kidney in normotensive and hypertensive rats Reviewed

Fabrice Bonnet, Christos Tikellis, Hiroshi Kawachi, Wendy C. Burns, Peter J. Wookey, Zemin Cao, Mark E. Cooper

Clinical and Experimental Hypertension 24 ( 5 ) 371 - 381 2002

Language：English Publishing type：Research paper (scientific journal)

Nephrin is a slit diaphragm protein and its expression in the developing kidney is largely unknown. In this study, we explored the expression of nephrin in the developmental kidney in spontaneously hypertensive (SHR) and in Wistar-Kyoto (WKY) rats at different time points, from day 5 after birth to adulthood. Real time RT-PCR, in situ hybridization and immunohistochemistry were used to assess and quantify gene and protein expression of nephrin in the kidney. SHR had hypertension at week 10 and albuminuria at week 20. Nephrin expression in both SHR and WKY increased from day 5 to adulthood. Furthermore, both gene and protein expression of nephrin were significantly lower in SHR after birth when compared to WKY at the same age. These findings suggest that both in normotensive and hypertensive rats, nephrin expression increased from birth to the adult age and that down-regulation of nephrin in SHR evident from the early developmental kidney to adulthood may contribute to the development of albuminuria in adult SHR.

DOI： 10.1081/CEH-120004798

Podocyte injuries exacerbate mesangial proliferative glomerulonephritis Reviewed

Y Morioka, H Koike, Y Ikezumi, Y Ito, A Oyanagi, F Gejyo, F Shimizu, H Kawachi

KIDNEY INTERNATIONAL 60 ( 6 ) 2192 - 2204 2001.12

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL SCIENCE INC

Background. From the observations of morphology seen in early phases of the experimental models of the irreversible mesangial proliferative glomerulonephritis, we hypothesized that podocyte injury is one of the important factors in bringing upon irreversible glomerular alterations. To verify this hypothesis, we investigated whether podocyte injury induced by puromycin aminonucleoside (PAN) injection affects the mesangial alterations of anti-Thy 1.1 glomerulonephritis.
Methods. Female Wistar rats were injected with 0.5 mg monoclonal antibody (mAb) 1-22-3 five days after the injection of 10 mg or 5 mg/100 g body weight (BW) of puromycin aminonucleoside (PAN), and sacrificed at 7 days or 8 weeks after the mAb 1-22-3 injection.
Results. Consecutive injections of 10 mg/100 g BW of PAN and mAb 1-22-3 caused the irreversible mesangial alteration with persistent proteinuria (at week 8, proteinuria 100.3 +/- 57.8 mg/24 h, matrix score 1.13 +/- 0.52, collagen type I score 2.04 +/- 0.53, mRNA for collagen type 1227 +/- 79% to the group with a single injection of 1-22-3). Although single injection of 5 mg/100 g BW of PAN was not capable of inducing abnormal proteinuria, consecutive injections of 5 mg/100 g BW of PAN and mAb 1-22-3 also caused irreversible mesangial alteration and persistent proteinuria.
Conclusions. Podocyte injury might be an important factor that exacerbates mesangial proliferation and mesangial matrix expansion. The irreversible mesangial alterations caused by consecutive injections of PAN and mAb 1-22-3 may be a novel model that could be used to analyze the mechanism of progressive mesangial alteration.

DOI： 10.1046/j.1523-1755.2001.00047.x