CCL2/MCP-1 and NFκB Gene Transcription in Remnant Kidneys after Physical Activity and Renoprotection

Kalev Ingrid, Pechter Ülle, Kõlvald Külli, Aunapuu Marina, Uhlinova Jana, Ots-Rosenberg Mai

Department of Anatomy, Tartu University, Tartu, Estonia.
Department of General and Molecular Pathology, Tartu University, Tartu, Estonia.
Department of Internal Medicine, Tartu University, Tartu, Estonia.

DOI: 10.4236/wjcd.2014.45032                

Abstract

Chronic kidney disease (CKD) is a progressive disease and affects approximately 10% of the population. The major late pathologic feature of CKD is interstitial fibrosis in the kidney characterized by extracellular matrix deposition but in early stage, several profibrotic and proinflammatory cytokines as well as growth factors are expressed. The renin-angiotensin and ET systems both play an important role in the pathogenesis of CKD and the blockade of these systems has been shown to suppress proinflammatory cytokines and to arrest the progression of CKD. We have demonstrated earlier also the renoprotective effect of physical activity on the experimental CKD progression (Pechter et al., 2003). Aim of the study was to investigate the effects of non-drug treatment, physical activity, to the extent of gene expression in experimental CKD and to compare with endothelin receptor blocker (ERB, sitaxentan) and standard nephroprotective drug, angiotensin receptor blocker (ARB, losartan) treatments. Expression of mRNA was assessed by real-time reverse transcription-polymerase chain reaction. CCL2/MCP-1 and nuclear factor-κB (NFκB) gene expression was measured in whole kidneys. Results revealed that CCL2/MCP-1 gene expression (data presented in poster presentation ASN Renal Week 2010, Pechter et al.) was increased in the 5/6 NPX rat kidneys, and the increase was lessened significantly after physical activity and losartan therapy. ERB treatment appeared less effective. Combined ARB and ERB treatment as well as drugs alone or physical therapy prevented the increase in systemic blood pressure, albuminuria and CCL2/MCP-1 as well as NFκB gene expression. We conclude that non-drug and drug treatments both were effective regarding the rate of the progression of experimental CKD measured by physiological and molecular biomarkers of chronic inflammation in kidney tissue.

Keywords

Remnant Kidney, Gene Transcription, Hypertension, Physical Activity, Renoprotection

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Zhang, Q.L. and Rothenbacher, D. (2010) Prevalence of Chronic Kidney Disease in Population-Based Studies: Systematic Review. BMC Public Health, 8, 117. http://dx.doi.org/10.1186/1471-2458-8-117
[2]	Castaldo, C., Di Meglio, F., Miraglia, R., Sacco, A.M., Romano, V., Bancone, C., et al. (2013) Cardiac Fibroblast-Derived Extracellular Matrix (Biomatrix) as a Model for the Studies of Cardiac Primitive Cell Biological Properties in Normal and Pathological Adult Human Heart. BioMed Research International, 2013, Article ID: 352370.
[3]	Taal, M.W., Zandi-Nejad, K., Weening, B., Shahsafaei, A., Kato, S., Lee, K.W., et al. (2000) Proinflammatory Gene Expression and Macrophage Recruitment in the Rat Remnant Kidney. Kidney International, 58, 1664-1676. http://dx.doi.org/10.1111/j.1523-1755.2000.00327.x
[4]	Kato, S., Luyckx, V.A., Ots, M., Lee, K.W., Ziai, F., Troy, J.L., et al. (1999) Renin-Angiotensin Blockade Lowers MCP-1 Expression in Diabetic Rats. Kidney International, 56, 1037-1048. http://dx.doi.org/10.1046/j.1523-1755.1999.00643.x
[5]	Ots, M., Pechter, U. and Tamm, A. (2000) Characteristics of Progressive Renal Disease. Clinica Chimica Acta, 297, 29-41. http://dx.doi.org/10.1016/S0009-8981(00)00231-X
[6]	Pechter, ü., Kalev, I., Kõlvald, K., Riispere, Z. and Rosenberg, M. (2009) Use of Water Immersion to Ameliorate the Progression of Chronic Experimental Kidney Disease. Scandinavian Journal of Laboratory Animal Science, 36, 11-16.
[7]	Benigni, A., Colosio, V., Brena, C., Bruzzi, I., Bertani, T. and Remuzzi, G. (1998) Unselective Inhibition of Endothelin Receptors Reduces Renal Dysfunction in Experimental Diabetes. Diabetes, 47, 450-456. http://dx.doi.org/10.2337/diabetes.47.3.450
[8]	Benigni, A., Corna, D., Maffi, R., Benedetti, G., Zoja, C. and Remuzzi, G. (1998) Renoprotective Effect of Contemporary Blocking of Angiotensin II and Endothelin-1 in Rats with Membranous Nephropathy. Kidney International, 54, 353-359. http://dx.doi.org/10.1046/j.1523-1755.1998.00011.x
[9]	Nabokov, A.V., Amann, K., Wessels, S., Munter, K., Wagner, J. and Ritz, E. (1999) Endothelin Receptor Antagonists Influence Cardiovascular Morphology in Uremic Rats. Kidney International, 55, 512-519. http://dx.doi.org/10.1046/j.1523-1755.1999.00290.x
[10]	Gross, M.L., El-Shakmak, A., Szabo, A., Koch, A., Kuhlmann, A., Munter, K., et al. (2003) ACE-Inhibitors but Not Endothelin Receptor Blockers Prevent Podocyte Loss in Early Diabetic Nephropathy. Diabetologia, 46, 856-868. http://dx.doi.org/10.1007/s00125-003-1106-8
[11]	Qiu, C. and Baylis, C. (1999) Endothelin and Angiotensin Mediate Most Glomerular Responses to Nitric Oxide Inhibition. Kidney International, 55, 2390-2396. http://dx.doi.org/10.1046/j.1523-1755.1999.00466.x
[12]	Ikeda, T., Ohta, H., Okada, M., Kawai, N., Nakao, R., Siegl, P.K., et al. (2000) Antihypertensive Effects of a Mixed Endothelin-A- and -B-Receptor Antagonist, J-104132, Were Augmented in the Presence of an AT1-Receptor Antagonist, MK-954. Journal of Cardiovascular Pharmacology, 36, S337-S341. http://dx.doi.org/10.1097/00005344-200036051-00098
[13]	Amann, K., Simonaviciene, A., Medwedewa, T., Koch, A., Orth, S., Gross, M.L., et al. (2001) Blood Pressure-Independent Additive Effects of Pharmacologic Blockade of the Renin-Angiotensin and Endothelin Systems on Progression in a Low-Renin Model of Renal Damage. Journal of the American Society of Nephrology, 12, 2572-2584.
[14]	Wolf, S.C., Sauter, G., Risler, T. and Brehm, B.R. (2005) Effects of Combined Endothelin and Angiotensin II Antagonism on Growth Factor-Induced Proliferation of Vascular Smooth Muscle Cells Isolated from Uremic Rats. Renal Failure, 27, 465-474. http://dx.doi.org/10.1081/JDI-65421
[15]	Gagliardini, E., Corna, D., Zoja, C., Sangalli, F., Carrara, F., Rossi, M., et al. (2009) Unlike Each Drug Alone, Lisinopril If Combined with Avosentan Promotes Regression of Renal Lesions in Experimental Diabetes. American Journal of Physiology. Renal Physiology, 297, F1448-F1456. http://dx.doi.org/10.1152/ajprenal.00340.2009
[16]	Ots, M. (1998) Characteristics of the Progression of Human and Experimental Glomerulopathies. Academic Dissertation.
[17]	Kohzuki, M., Kamimoto, M., Wu, X.M., Xu, H.L., Kawamura, T., Mori, N., et al. (2001) Renal Protective Effects of Chronic Exercise and Antihypertensive Therapy in Hypertensive Rats with Chronic Renal Failure. Journal of Hypertension, 19, 1877-1882. http://dx.doi.org/10.1097/00004872-200110000-00024
[18]	Ishikawa, Y., Gohda, T., Tanimoto, M., Omote, K., Furukawa, M., Yamaguchi, S., et al. (2012) Effect of Exercise on Kidney Function, Oxidative Stress, and Inflammation in Type 2 Diabetic KK-A(y) Mice. Experimental Diabetes Research, 2012, Article ID: 702948. http://dx.doi.org/10.1155/2012/702948
[19]	Vaziri, N.D., Bai, Y., Ni, Z., Quiroz, Y., Pandian, R. and Rodriguez-Iturbe, B. (2007) Intra-Renal Angiotensin II/AT1 Receptor, Oxidative Stress, Inflammation, and Progressive Injury in Renal Mass Reduction. Journal of Pharmacology and Experimental Therapeutics, 323, 85-93. http://dx.doi.org/10.1124/jpet.107.123638
[20]	Cao, Z., Cooper, M.E., Wu, L.L., Cox, A.J., Jandeleit-Dahm, K., Kelly, D.J., et al. (2000) Blockade of the Renin-Angiotensin and Endothelin Systems on Progressive Renal Injury. Hypertension, 36, 561-568. http://dx.doi.org/10.1161/01.HYP.36.4.561
[21]	Orth, S.R., Odoni, G., Karkoszka, H., Ogata, H., Viedt, C., Amann, K., et al. (2003) Combination Treatment with an ET(A)-Receptor Blocker and an ACE Inhibitor Is Not Superior to the Respective Monotherapies in Attenuating Chronic Transplant Vasculopathy in Different Aorta Allotransplantation Rat Models. Nephrology Dialysis Transplantation, 18, 62-69. http://dx.doi.org/10.1093/ndt/18.1.62
[22]	Muller, D.N., Dechend, R., Mervaala, E.M., Park, J.K., Schmidt, F., Fiebeler, A., et al. (2000) NF-KappaB Inhibition Ameliorates Angiotensin II-Induced Inflammatory Damage in Rats. Hypertension, 35, 193-201. http://dx.doi.org/10.1161/01.HYP.35.1.193