Podocyte loss and albuminuria of KK-Ay mouse: A spontaneous animal model for human type 2 diabetic nephropathy
Author(s)
Yuji Ishikawa,
Takamichi Ito,
Mitsuo Tanimoto,
Shinji Hagiwara,
Masako Furukawa,
Saori Yamaguchi,
Keisuke Omote,
Katsuhiko Asanuma,
Tomohito Gohda,
Yoshio Shimizu,
Kazuhiko Funabiki,
Satoshi Horikoshi,
Yasuhiko Tomino*
Affiliation(s)
Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Juntendo University, Tokyo, Japan.
Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Juntendo University, Tokyo, Japan.
ABSTRACT
Podocyte loss was well known in type 2 diabetic nephropathy patients. The objective of the present study was to determine the number of podocytes and the degree of albuminuria in diabetic KK-Ay/Ta (KK-Ay) mice which had been reported as diabetic nephropathy model. Diabetic KK-Ay mice, diabetic KK/Ta mice and non-diabetic BALB/cA Jcl (BALB/cA) mice were studied. We analyzed glomerular lesions in all mice by morphometric analysis and immunofluorescence to determine the number of podocytes. Level of urinary albumin was also measured. Glomerular enlargement and mesangial expansion were observed in KK-Ay mice. Mean number of podocytes per glomerulus (NG pod) in diabetic KK-Ay mice was significantly lower than that in non-diabetic BALB/cA mice. Mean NG pod/glomerular area (GA) per glomerulus was also significantly decreased in diabetic KK-Ay mice. The level of urinary albumin/creatinine ratio (ACR) in diabetic KK-Ay mice was significantly higher than that in non-diabetic BALB/cA mice. These data suggest that podocyte loss might induce albuminuria in KK-Ay mice. This finding confirmed our previous report that KK-Ay mice, especially in terms of histological findings, are a suitable animal model for glomerular injury in type 2 diabetic nephropathy.
Podocyte loss was well known in type 2 diabetic nephropathy patients. The objective of the present study was to determine the number of podocytes and the degree of albuminuria in diabetic KK-Ay/Ta (KK-Ay) mice which had been reported as diabetic nephropathy model. Diabetic KK-Ay mice, diabetic KK/Ta mice and non-diabetic BALB/cA Jcl (BALB/cA) mice were studied. We analyzed glomerular lesions in all mice by morphometric analysis and immunofluorescence to determine the number of podocytes. Level of urinary albumin was also measured. Glomerular enlargement and mesangial expansion were observed in KK-Ay mice. Mean number of podocytes per glomerulus (NG pod) in diabetic KK-Ay mice was significantly lower than that in non-diabetic BALB/cA mice. Mean NG pod/glomerular area (GA) per glomerulus was also significantly decreased in diabetic KK-Ay mice. The level of urinary albumin/creatinine ratio (ACR) in diabetic KK-Ay mice was significantly higher than that in non-diabetic BALB/cA mice. These data suggest that podocyte loss might induce albuminuria in KK-Ay mice. This finding confirmed our previous report that KK-Ay mice, especially in terms of histological findings, are a suitable animal model for glomerular injury in type 2 diabetic nephropathy.
Cite this paper
Ishikawa, Y. , Ito, T. , Tanimoto, M. , Hagiwara, S. , Furukawa, M. , Yamaguchi, S. , Omote, K. , Asanuma, K. , Gohda, T. , Shimizu, Y. , Funabiki, K. , Horikoshi, S. and Tomino, Y. (2012) Podocyte loss and albuminuria of KK-Ay mouse: A spontaneous animal model for human type 2 diabetic nephropathy. Journal of Diabetes Mellitus, 2, 346-352. doi: 10.4236/jdm.2012.23054.
Ishikawa, Y. , Ito, T. , Tanimoto, M. , Hagiwara, S. , Furukawa, M. , Yamaguchi, S. , Omote, K. , Asanuma, K. , Gohda, T. , Shimizu, Y. , Funabiki, K. , Horikoshi, S. and Tomino, Y. (2012) Podocyte loss and albuminuria of KK-Ay mouse: A spontaneous animal model for human type 2 diabetic nephropathy. Journal of Diabetes Mellitus, 2, 346-352. doi: 10.4236/jdm.2012.23054.
References
[1] Rudberg, S. and Osterby, R. (1998) Diabetic glomerulopathy in young IDDM patients, preventive and diagnostic aspects. Hormone Research, 50, 17-22. doi:10.1159/000053097 [2] Osterby, R. (1992) Glomerular structural changes in type 1 (insulin-dependent) diabetes mellitus: Causes, consequences, and prevention. Diabetologia, 35, 803-812. doi:10.1007/BF00399925 [3] Osterby, R. (1996) Lessons from kidney biopsies. Diabetes/Metabolism Reviews, 12, 151-174. doi:10.1002/(SICI)1099-0895(199610)12:3<151::AID-DMR162>3.0.CO;2-1 [4] Hishiki, T., Shirato, I., Takahashi, Y., Funabiki, K., Horikoshi, S. and Tomino, Y. (2001) Podocyte injury predicts prognosis in patients with IgA nephropathy using a small amount of renal biopsy tissue. Kidney & Blood Pressure Research, 24, 99-104. doi:10.1159/000054214 [5] Lemley, K.V., Lafayette, R.A., Safai, M., Derby, G., Blouch, A., Squarer, A. and Myers, B.D. (2002) Podocytopenia and disease severity in IgA nephropathy. Kidney International, 61, 1475-1485. doi:10.1046/j.1523-1755.2002.00269.x [6] Macedo, C.S., Lerco, M.M., Capelletti, S.M., Silva, R.J., Pinheiro, D.O. and Spadella C.T. (2007) Reduction of podocytes number in late diabetic alloxan nephropathy: Prevention by glycemic control. Acta Cirurgica Brasileira, 22, 337-341. doi:10.1590/S0102-86502007000500003 [7] Kondo, K., Nozawa, K., Tomita, T. and Ezaki, K. (1957) Inbred strains resulting from Japanese mice. Bulletin of the Experimental Animals, 6, 107-112. [8] Taketomi, S., Ikeda, H., Ishikawa, E. and Iwatsuka, H. (1982) Determination of overall insulin sensitivity in diabetic mice, KK. Hormone and Metabolic Research, 14, 14-18. doi:10.1055/s-2007-1018909 [9] Matsuo, T. and Shino, A. (1972) Induction of diabetic alterations by goldthioglucose-obesity in KK, ICR and C57BL mice. Diabetologia, 8, 391-397. doi:10.1007/BF01212165 [10] Shike, T., Gohda, T., Tanimoto, M., Funabiki, K., Horikoshi, S., Hirose, S., Shirai, T. and Tomino, T. (2005) Chromosomal mapping of a quantitative trait locus for the development of albuminuria in diabetic KK/Ta mice. Nephrology Dialysis Transplantation, 20, 879-885. doi:10.1093/ndt/gfh665 [11] Ito, T., Tanimoto, M., Matsumoto, M., Yamada, K., Kaneko, S., Msatsumoto, M., Obayashi, K., Hagiwara, S., Murakoshi, M., Aoki, T., Wakabayashi, M., Gohda, T., Funabiki, K., Maeda, K., Horikoshi, S. and Tomino, Y., (2006) Glomerular changes in the KK-Ay/Ta mouse: A possible model for human type 2 diabetic nephropathy. Nephrology, 11, 29-35. doi:10.1111/j.1440-1797.2006.00543.x [12] Okazaki, M., Saito, Y., Udaka, Y., Maruyama, M., Murakami, H., Ota, S., Kikuchi, T. and Oguchi, K. (2002) Diabetic nephropathy in KK and KK-Ay mice. Experimental Animals, 51, 191-196. doi:10.1538/expanim.51.191 [13] Weibel, E.R. (1979) Stereological Methods: Practical Me- thods for Biological Morphometry. Academic Press, Inc., London. [14] Cohen, M.P. and Ziyadeh, F. N. (1996) Role of amadori-modified nonenzymatically glycated serum proteins in the pathogenesis of diabetic nephropathy. Journal of the American Society of Nephrology, 7, 183-190. [15] Fukami, K., Ueda, S., Yamagishi, S., Kato, S., Inagaki, Y., Takeuchi, M., Motoyama, Y., Bucala, R., Iida, S., Tamaki, K., Imaizumi, T. and Cooper, M.E. (2004) AGEs activate mesangial TGF-beta-smad signaling via an angiotensin II type I receptor interaction. Kidney International, 66, 2137-2147. doi:10.1111/j.1523-1755.2004.66004.x [16] Pagtalunan, M.E., Miller, P.L., Jumping-Eagle, S., Nelson, R.G., Myers, B.D., Rennke, H.G., Coplon, N.S. and Meyer, T.W. (1997) Podocyte loss and progressive glomerular injury in type II diabetes. Journal of Clinical Investigation, 99, 342-348. doi:10.1172/JCI119163 [17] Lemley, K.V. (2008) Diabetes and chronic kidney disease: Lessons from the Pima Indians. Pediatric Nephrology, 23, 1933-1940. doi:10.1007/s00467-008-0763-8 [18] Asanuma, K., Campbell, K.N., Kim, K., Faul, C. and Mundel, P. (2007) Nuclear relocation of the nephrin and CD2AP-binding protein dendrin promotes apoptosis of podocytes. Proceedings of the National Academy of Sciences USA, 104, 10134-10139. doi:10.1073/pnas.0700917104 [19] Asanuma, K., Yanagida-Asanuma, E., Takagi, M., Kodama, F. and Tomino, Y. (2007) The role of podocytes in proteinuria. Nephrology, 12, 15-20. doi:10.1111/j.1440-1797.2007.00876.x [20] Gu, L., Hagiwara, S., Fan, Q., Tanimoto, M., Kobata, M., Yamashita, M., Gohda, T., Ni, Z., Horikoshi, S. and Tomino, Y. (2006) Role of receptor for advanced glycation end-products-induced monocyte chemoattractant protein-1 expression in differentiated mouse podocytes. Nephrology Dialysis Transplantation, 21, 299-313. doi:10.1093/ndt/gfi210 [21] Nakamura, T., Ushiyama, C., Suzuki, S., Hara, M., Shimada, N., Ebihara, I. and Koide, H. (2000) Urinary excretion of podocytes in patients with diabetic nephropathy. Nephrology Dialysis Transplantation, 15, 1379-1383. doi:10.1093/ndt/15.9.1379 [22] Hara, M., Yanagihara, T., Takada, T., Itoh, M., Matsuno, M., Yamamoto, T. and Kihara, I. (1998) Urinary excretion of podocytes reflects disease activity in children with glomerulonephritis. American Journal of Nephrology, 18, 35-41. doi:10.1159/000013302 [23] Kretzler, M. (2005) Role of podocytes in focal sclerosis: Defining the point of no return. Journal of the American Society of Nephrology, 16, 2830-2832. doi:10.1681/ASN.2005080841 [24] Lemley, K.V., Lafayette, R.A., Safai, M., Derby, G., Blouch, K., Squarer, A. and Myers, B.D. (2002) Podocytopenia and disease severity in IgA nephropathy. Kidney International, 61, 1475-1485. doi:10.1046/j.1523-1755.2002.00269.x
[1] Rudberg, S. and Osterby, R. (1998) Diabetic glomerulopathy in young IDDM patients, preventive and diagnostic aspects. Hormone Research, 50, 17-22. doi:10.1159/000053097 [2] Osterby, R. (1992) Glomerular structural changes in type 1 (insulin-dependent) diabetes mellitus: Causes, consequences, and prevention. Diabetologia, 35, 803-812. doi:10.1007/BF00399925 [3] Osterby, R. (1996) Lessons from kidney biopsies. Diabetes/Metabolism Reviews, 12, 151-174. doi:10.1002/(SICI)1099-0895(199610)12:3<151::AID-DMR162>3.0.CO;2-1 [4] Hishiki, T., Shirato, I., Takahashi, Y., Funabiki, K., Horikoshi, S. and Tomino, Y. (2001) Podocyte injury predicts prognosis in patients with IgA nephropathy using a small amount of renal biopsy tissue. Kidney & Blood Pressure Research, 24, 99-104. doi:10.1159/000054214 [5] Lemley, K.V., Lafayette, R.A., Safai, M., Derby, G., Blouch, A., Squarer, A. and Myers, B.D. (2002) Podocytopenia and disease severity in IgA nephropathy. Kidney International, 61, 1475-1485. doi:10.1046/j.1523-1755.2002.00269.x [6] Macedo, C.S., Lerco, M.M., Capelletti, S.M., Silva, R.J., Pinheiro, D.O. and Spadella C.T. (2007) Reduction of podocytes number in late diabetic alloxan nephropathy: Prevention by glycemic control. Acta Cirurgica Brasileira, 22, 337-341. doi:10.1590/S0102-86502007000500003 [7] Kondo, K., Nozawa, K., Tomita, T. and Ezaki, K. (1957) Inbred strains resulting from Japanese mice. Bulletin of the Experimental Animals, 6, 107-112. [8] Taketomi, S., Ikeda, H., Ishikawa, E. and Iwatsuka, H. (1982) Determination of overall insulin sensitivity in diabetic mice, KK. Hormone and Metabolic Research, 14, 14-18. doi:10.1055/s-2007-1018909 [9] Matsuo, T. and Shino, A. (1972) Induction of diabetic alterations by goldthioglucose-obesity in KK, ICR and C57BL mice. Diabetologia, 8, 391-397. doi:10.1007/BF01212165 [10] Shike, T., Gohda, T., Tanimoto, M., Funabiki, K., Horikoshi, S., Hirose, S., Shirai, T. and Tomino, T. (2005) Chromosomal mapping of a quantitative trait locus for the development of albuminuria in diabetic KK/Ta mice. Nephrology Dialysis Transplantation, 20, 879-885. doi:10.1093/ndt/gfh665 [11] Ito, T., Tanimoto, M., Matsumoto, M., Yamada, K., Kaneko, S., Msatsumoto, M., Obayashi, K., Hagiwara, S., Murakoshi, M., Aoki, T., Wakabayashi, M., Gohda, T., Funabiki, K., Maeda, K., Horikoshi, S. and Tomino, Y., (2006) Glomerular changes in the KK-Ay/Ta mouse: A possible model for human type 2 diabetic nephropathy. Nephrology, 11, 29-35. doi:10.1111/j.1440-1797.2006.00543.x [12] Okazaki, M., Saito, Y., Udaka, Y., Maruyama, M., Murakami, H., Ota, S., Kikuchi, T. and Oguchi, K. (2002) Diabetic nephropathy in KK and KK-Ay mice. Experimental Animals, 51, 191-196. doi:10.1538/expanim.51.191 [13] Weibel, E.R. (1979) Stereological Methods: Practical Me- thods for Biological Morphometry. Academic Press, Inc., London. [14] Cohen, M.P. and Ziyadeh, F. N. (1996) Role of amadori-modified nonenzymatically glycated serum proteins in the pathogenesis of diabetic nephropathy. Journal of the American Society of Nephrology, 7, 183-190. [15] Fukami, K., Ueda, S., Yamagishi, S., Kato, S., Inagaki, Y., Takeuchi, M., Motoyama, Y., Bucala, R., Iida, S., Tamaki, K., Imaizumi, T. and Cooper, M.E. (2004) AGEs activate mesangial TGF-beta-smad signaling via an angiotensin II type I receptor interaction. Kidney International, 66, 2137-2147. doi:10.1111/j.1523-1755.2004.66004.x [16] Pagtalunan, M.E., Miller, P.L., Jumping-Eagle, S., Nelson, R.G., Myers, B.D., Rennke, H.G., Coplon, N.S. and Meyer, T.W. (1997) Podocyte loss and progressive glomerular injury in type II diabetes. Journal of Clinical Investigation, 99, 342-348. doi:10.1172/JCI119163 [17] Lemley, K.V. (2008) Diabetes and chronic kidney disease: Lessons from the Pima Indians. Pediatric Nephrology, 23, 1933-1940. doi:10.1007/s00467-008-0763-8 [18] Asanuma, K., Campbell, K.N., Kim, K., Faul, C. and Mundel, P. (2007) Nuclear relocation of the nephrin and CD2AP-binding protein dendrin promotes apoptosis of podocytes. Proceedings of the National Academy of Sciences USA, 104, 10134-10139. doi:10.1073/pnas.0700917104 [19] Asanuma, K., Yanagida-Asanuma, E., Takagi, M., Kodama, F. and Tomino, Y. (2007) The role of podocytes in proteinuria. Nephrology, 12, 15-20. doi:10.1111/j.1440-1797.2007.00876.x [20] Gu, L., Hagiwara, S., Fan, Q., Tanimoto, M., Kobata, M., Yamashita, M., Gohda, T., Ni, Z., Horikoshi, S. and Tomino, Y. (2006) Role of receptor for advanced glycation end-products-induced monocyte chemoattractant protein-1 expression in differentiated mouse podocytes. Nephrology Dialysis Transplantation, 21, 299-313. doi:10.1093/ndt/gfi210 [21] Nakamura, T., Ushiyama, C., Suzuki, S., Hara, M., Shimada, N., Ebihara, I. and Koide, H. (2000) Urinary excretion of podocytes in patients with diabetic nephropathy. Nephrology Dialysis Transplantation, 15, 1379-1383. doi:10.1093/ndt/15.9.1379 [22] Hara, M., Yanagihara, T., Takada, T., Itoh, M., Matsuno, M., Yamamoto, T. and Kihara, I. (1998) Urinary excretion of podocytes reflects disease activity in children with glomerulonephritis. American Journal of Nephrology, 18, 35-41. doi:10.1159/000013302 [23] Kretzler, M. (2005) Role of podocytes in focal sclerosis: Defining the point of no return. Journal of the American Society of Nephrology, 16, 2830-2832. doi:10.1681/ASN.2005080841 [24] Lemley, K.V., Lafayette, R.A., Safai, M., Derby, G., Blouch, K., Squarer, A. and Myers, B.D. (2002) Podocytopenia and disease severity in IgA nephropathy. Kidney International, 61, 1475-1485. doi:10.1046/j.1523-1755.2002.00269.x