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Heat shock proteins in the kidney

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Abstract

Heat shock proteins (Hsps) are essential to cell survival through their function as protein chaperones. The role they play in kidney health and disease is varied. Hsp induction may be either beneficial or detrimental to the kidney, depending on the specific Hsp, type of cell, and context. This review addresses the role of Hsps in the kidney, including during development, as osmoprotectants, and in various kidney disease models. Heat shock transcription factor, activated by a stress on renal cells, induces Hsp elaboration and separately regulates immune responses that can contribute to renal injury. Induced Hsps in the intracellular compartment are mostly beneficial in the kidney by stabilizing and restoring cell architecture and function through acting as protein chaperones. Intracellular Hsps also inhibit apoptosis and facilitate cell proliferation, preserving renal tubule viability after acute injury, but enhancing progression of cystic kidney disease and malignancy. Induced Hsps in the extracellular compartment, either circulating or located on outer cell membranes, are mainly detrimental through enhancing inflammation pathways to injury. Correctly harnessing these stress proteins promises the opportunity to alter the course of acute and chronic kidney disease.

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References

  1. Nover L (ed) (1991) Heat shock response. CRC Press, Boca Raton, FL

  2. Le Masson F, Christians E (2011) HSFs and regulation of Hsp70.1 (Hspa1b) in oocytes and preimplantation embryos: new insights brought by transgenic and knockout mouse models. Cell Stress Chaperones 16:275–285

    Article  CAS  PubMed  Google Scholar 

  3. Sreedharan R, Chen S, Miller M, Haribhai D, Williams CB, Van Why SK (2014) Mice with an absent stress response are protected against ischemic renal injury. Kidney Int 86:515–524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gaudio KM, Thulin G, Mann A, Kashgarian M, Siegel NJ (1998) Role of heat stress response in the tolerance of immature renal tubules to anoxia. Am J Physiol 274:F1029–1036

    CAS  PubMed  Google Scholar 

  5. Vicencio A, Bidmon B, Ryu J, Reidy K, Thulin G, Mann A, Gaudio KM, Kashgarian M, Siegel NJ (2003) Developmental expression of HSP-72 and ischemic tolerance of the immature kidney. Pediatr Nephrol 18:85–91

    PubMed  Google Scholar 

  6. D'Souza SM, Brown IR (1998) Constitutive expression of heat shock proteins Hsp90, Hsc70, Hsp70 and Hsp60 in neural and non-neural tissues of the rat during postnatal development. Cell Stress Chaperones 3:188–199

    Article  PubMed  PubMed Central  Google Scholar 

  7. Kennedy D, Jager R, Mosser DD, Samali (2014) A Regulation of apoptosis by heat shock proteins. IUBMB Life 66:327–338

    Article  CAS  PubMed  Google Scholar 

  8. Velichko AK, Markova EN, Petrova NV, Razin SV, Kantidze OL (2013) Mechanisms of heat shock response in mammals. Cell Mol Life Sci 70:4229–4241

    Article  CAS  PubMed  Google Scholar 

  9. Verghese J, Abrams J, Wang Y, Morano KA (2012) Biology of the heat shock response and protein chaperones: budding yeast (Saccharomyces cerevisiae) as a model system. Microbiol Mol Biol Rev 76:115–158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Emami A, Schwartz JH, Borkan SC (1991) Transient ischemia or heat stress induces a cytoprotectant protein in rat kidney. Am J Physiol 260:F479–485

    CAS  PubMed  Google Scholar 

  11. Muller E, Neuhofer W, Ohno A, Rucker S, Thurau K, Beck FX (1996) Heat shock proteins HSP25, HSP60, HSP72, HSP73 in isoosmotic cortex and hyperosmotic medulla of rat kidney. Pflugers Arch 431:608–617

    Article  CAS  PubMed  Google Scholar 

  12. Khan W, McGuirt JP, Sens MA, Sens DA, Todd JH (1996) Expression of heat shock protein 27 in developing and adult human kidney. Toxicol Lett 84:69–79

    Article  CAS  PubMed  Google Scholar 

  13. Xu Q, Ganju L, Fawcett TW, Holbrook NJ (1996) Vasopressin-induced heat shock protein expression in renal tubular cells. Lab Investig 74:178–187

    CAS  PubMed  Google Scholar 

  14. Cowley BD Jr, Muessel MJ, Douglass D, Wilkins W (1995) In vivo and in vitro osmotic regulation of HSP-70 and prostaglandin synthase gene expression in kidney cells. Am J Physiol 269:F854–862

    CAS  PubMed  Google Scholar 

  15. Medina R, Cantley L, Spokes K, Epstein FH (1996) Effect of water diuresis and water restriction on expression of HSPs-27, -60 and -70 in rat kidney. Kidney Int 50:1191–1194

    Article  CAS  PubMed  Google Scholar 

  16. Rauchman MI, Pullman J, Gullans SR (1997) Induction of molecular chaperones by hyperosmotic stress in mouse inner medullary collecting duct cells. Am J Physiol 273:F9–17

    CAS  PubMed  Google Scholar 

  17. Kojima R, Randall J, Brenner BM, Gullans SR (1996) Osmotic stress protein 94 (Osp94). A new member of the Hsp110/SSE gene subfamily. J Biol Chem 271:12327–12332

    Article  CAS  PubMed  Google Scholar 

  18. Santos BC, Chevaile A, Kojima R, Gullans SR (1998) Characterization of the Hsp110/SSE gene family response to hyperosmolality and other stresses. Am J Physiol 274:F1054–1061

    CAS  PubMed  Google Scholar 

  19. Cai Q, Ferraris JD, Burg MB (2004) Greater tolerance of renal medullary cells for a slow increase in osmolality is associated with enhanced expression of HSP70 and other osmoprotective genes. Am J Physiol Renal Physiol 286:F58–67

    Article  CAS  PubMed  Google Scholar 

  20. Valkova N, Kultz D (2006) Constitutive and inducible stress proteins dominate the proteome of the murine inner medullary collecting duct-3 (mIMCD3) cell line. Biochim Biophys Acta 1764:1007–1020

    Article  CAS  PubMed  Google Scholar 

  21. Kojima R, Randall JD, Ito E, Manshio H, Suzuki Y, Gullans SR (2004) Regulation of expression of the stress response gene, Osp94: identification of the tonicity response element and intracellular signalling pathways. Biochem J 380:783–794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kim CH, Kim YC, Choi BY, Lee HS, Oh SH, Kim YH (2012) Expression of osmotic stress protein 94 in murine endolymphatic hydrops model. Acta Otolaryngol 132(Suppl 1):S118–123

    Article  CAS  PubMed  Google Scholar 

  23. Van Why SK, Mann AS, Thulin G, Zhu XH, Kashgarian M, Siegel NJ (1994) Activation of heat-shock transcription factor by graded reductions in renal ATP, in vivo, in the rat. J Clin Invest 94:1518–1523

    Article  PubMed  PubMed Central  Google Scholar 

  24. Van Why SK, Hildebrandt F, Ardito T, Mann AS, Siegel NJ, Kashgarian M (1992) Induction and intracellular localization of HSP-72 after renal ischemia. Am J Physiol 263:F769–775

    PubMed  Google Scholar 

  25. Aufricht C, Ardito T, Thulin G, Kashgarian M, Siegel NJ, Van Why SK (1998) Heat-shock protein 25 induction and redistribution during actin reorganization after renal ischemia. Am J Physiol 274:F215–222

    CAS  PubMed  Google Scholar 

  26. van Why SK, Kim S, Geibel J, Seebach FA, Kashgarian M, Siegel NJ (1999) Thresholds for cellular disruption and activation of the stress response in renal epithelia. Am J Physiol 277:F227–234

    PubMed  Google Scholar 

  27. Molitoris BA (1991) New insights into the cell biology of ischemic acute renal failure. J Am Soc Nephrol 1:1263–1270

    CAS  PubMed  Google Scholar 

  28. Molitoris BA, Dahl R, Hosford M (1996) Cellular ATP depletion induces disruption of the spectrin cytoskeletal network. Am J Physiol 271:F790–798

    CAS  PubMed  Google Scholar 

  29. Van Why SK, Mann AS, Ardito T, Siegel NJ, Kashgarian M (1994) Expression and molecular regulation of Na(+)-K(+)-ATPase after renal ischemia. Am J Physiol 267:F75–85

    PubMed  Google Scholar 

  30. Aufricht C, Lu E, Thulin G, Kashgarian M, Siegel NJ, Van Why SK (1998) ATP releases HSP-72 from protein aggregates after renal ischemia. Am J Physiol 274:F268–274

    CAS  PubMed  Google Scholar 

  31. Riordan M, Sreedharan R, Wang S, Thulin G, Mann A, Stankewich M, Van Why S, Kashgarian M, Siegel NJ (2005) HSP70 binding modulates detachment of Na-K-ATPase following energy deprivation in renal epithelial cells. Am J Physiol Renal Physiol 288:F1236–1242

    Article  CAS  PubMed  Google Scholar 

  32. Van Why SK, Mann AS, Ardito T, Thulin G, Ferris S, Macleod MA, Kashgarian M, Siegel NJ (2003) Hsp27 associates with actin and limits injury in energy depleted renal epithelia. J Am Soc Nephrol 14:98–106

    Article  PubMed  Google Scholar 

  33. Riordan M, Garg V, Thulin G, Kashgarian M, Siegel NJ (2004) Differential inhibition of HSP72 and HSP25 produces profound impairment of cellular integrity. J Am Soc Nephrol 15:1557–1566

    Article  CAS  PubMed  Google Scholar 

  34. Sreedharan R, Riordan M, Thullin G, Van Why S, Siegel NJ, Kashgarian M (2011) The maximal cytoprotective function of the heat shock protein 27 is dependent on heat shock protein 70. Biochim Biophys Acta 1813:129–135

    Article  CAS  PubMed  Google Scholar 

  35. Chen SW, Kim M, Song JH, Park SW, Wells D, Brown K, Belleroche J, D'Agati VD, Lee HT (2009) Mice that overexpress human heat shock protein 27 have increased renal injury following ischemia reperfusion. Kidney Int 75:499–510

    Article  CAS  PubMed  Google Scholar 

  36. Kim M, Park SW, Chen SW, Gerthoffer WT, D'Agati VD, Lee HT (2010) Selective renal overexpression of human heat shock protein 27 reduces renal ischemia-reperfusion injury in mice. Am J Physiol Renal Physiol 299:F347–358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sreedharan R, Riordan M, Wang S, Thulin G, Kashgarian M, Siegel NJ (2005) Reduced tolerance of immature renal tubules to anoxia by HSF-1 decoy. Am J Physiol Renal Physiol 288:F322–326

    Article  CAS  PubMed  Google Scholar 

  38. Fekete A, Treszl A, Toth-Heyn P, Vannay A, Tordai A, Tulassay T, Vasarhelyi B (2003) Association between heat shock protein 72 gene polymorphism and acute renal failure in premature neonates. Pediatr Res 54:452–455

    Article  CAS  PubMed  Google Scholar 

  39. Vasarhelyi B, Toth-Heyn P, Treszl A, Tulassay T (2005) Genetic polymorphisms and risk for acute renal failure in preterm neonates. Pediatr Nephrol 20:132–135

    Article  PubMed  Google Scholar 

  40. Sato A, Asano T, Ito K (2012) 17-Allylamino-17-demethoxygeldanamycin and ritonavir inhibit renal cancer growth by inhibiting the expression of heat shock factor-1. Int J Oncol 41:46–52

    CAS  PubMed  Google Scholar 

  41. Roigas J, Wallen ES, Loening SA, Moseley PL (1998) Heat shock protein (HSP72) surface expression enhances the lysis of a human renal cell carcinoma by IL-2 stimulated NK cells. Adv Exp Med Biol 451:225–229

    Article  CAS  PubMed  Google Scholar 

  42. Seeger-Nukpezah T, Proia DA, Egleston BL, Nikonova AS, Kent T, Cai KQ, Hensley HH, Ying W, Chimmanamada D, Serebriiskii IG, Golemis EA (2013) Inhibiting the HSP90 chaperone slows cyst growth in a mouse model of autosomal dominant polycystic kidney disease. Proc Natl Acad Sci U S A 110:12786–12791

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Jones TJ, Adapala RK, Geldenhuys WJ, Bursley C, AbouAlaiwi WA, Nauli SM, Thodeti CK (2012) Primary cilia regulates the directional migration and barrier integrity of endothelial cells through the modulation of hsp27-dependent actin cytoskeletal organization. J Cell Physiol 227:70–76

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ma L, Liu Y, El-Achkar TM, Wu XR (2012) Molecular and cellular effects of Tamm-Horsfall protein mutations and their rescue by chemical chaperones. J Biol Chem 287:1290–1305

    Article  CAS  PubMed  Google Scholar 

  45. Smoyer WE, Gupta A, Mundel P, Ballew JD, Welsh MJ (1996) Altered expression of glomerular heat shock protein 27 in experimental nephrotic syndrome. J Clin Invest 97:2697–2704

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Smoyer WE, Ransom RF (2002) Hsp27 regulates podocyte cytoskeletal changes in an in vitro model of podocyte process retraction. FASEB J 16:315–326

    Article  CAS  PubMed  Google Scholar 

  47. Eichler TE, Ransom RF, Smoyer WE (2005) Differential induction of podocyte heat shock proteins by prolonged single and combination toxic metal exposure. Toxicol Sci 84:120–128

    Article  CAS  PubMed  Google Scholar 

  48. Ransom RF, Vega-Warner V, Smoyer WE, Klein J (2005) Differential proteomic analysis of proteins induced by glucocorticoids in cultured murine podocytes. Kidney Int 67:1275–1285

    Article  CAS  PubMed  Google Scholar 

  49. Guess AJ, Ayoob R, Chanley M, Manley J, Cajaiba MM, Agrawal S, Pengal R, Pyle AL, Becknell B, Kopp JB, Ronkina N, Gaestel M, Benndorf R, Smoyer WE (2013) Crucial roles of the protein kinases MK2 and MK3 in a mouse model of glomerulonephritis. PLoS One 8:e54239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lang A, Benke D, Eitner F, Engel D, Ehrlich S, Breloer M, Hamilton-Williams E, Specht S, Hoerauf A, Floege J, von Bonin A, Kurts C (2005) Heat shock protein 60 is released in immune-mediated glomerulonephritis and aggravates disease: in vivo evidence for an immunologic danger signal. J Am Soc Nephrol 16:383–391

    Article  CAS  PubMed  Google Scholar 

  51. Pieper M, Rupprecht HD, Bruch KM, De Heer E, Schocklmann HO (2000) Requirement of heat shock protein 90 in mesangial cell mitogenesis. Kidney Int 58:2377–2389

    Article  CAS  PubMed  Google Scholar 

  52. Razzaque MS, Kumatori A, Harada T, Taguchi T (1998) Coexpression of collagens and collagen-binding heat shock protein 47 in human diabetic nephropathy and IgA nephropathy. Nephron 80:434–443

    Article  CAS  PubMed  Google Scholar 

  53. Pablos JL, Carreira PE, Martin-Villa JM, Montalvo G, Arnaiz-Villena A, Gomez-Reino JJ (1995) Polymorphism of the heat-shock protein gene HSP70-2 in systemic lupus erythematosus. Br J Rheumatol 34:721–723

    Article  CAS  PubMed  Google Scholar 

  54. Shimp SK 3rd, Chafin CB, Regna NL, Hammond SE, Read MA, Caudell DL, Rylander M, Reilly CM (2012) Heat shock protein 90 inhibition by 17-DMAG lessens disease in the MRL/lpr mouse model of systemic lupus erythematosus. Cell Mol Immunol 9:255–266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Liu B, Dai J, Zheng H, Stoilova D, Sun S, Li Z (2003) Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases. Proc Natl Acad Sci U S A 100:15824–15829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Kenderov A, Minkova V, Mihailova D, Giltiay N, Kyurkchiev S, Kehayov I, Kazatchkine M, Kaveri S, Pashov A (2002) Lupus-specific kidney deposits of HSP90 are associated with altered IgG idiotypic interactions of anti-HSP90 autoantibodies. Clin Exp Immunol 129:169–176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kulkarni OP, Ryu M, Kantner C, Sardy M, Naylor D, Lambert D, Brown R, Anders HJ (2012) Recombinant chaperonin 10 suppresses cutaneous lupus and lupus nephritis in MRL-(Fas)lpr mice. Nephrol Dial Transplant 27:1358–1367

    Article  CAS  PubMed  Google Scholar 

  58. Sanchez E, Abelson AK, Sabio JM, Gonzalez-Gay MA, Ortego-Centeno N, Jimenez-Alonso J, de Ramon E, Sanchez-Roman J, Lopez-Nevot MA, Gunnarsson I, Svenungsson E, Sturfelt G, Truedsson L, Jonsen A, Gonzalez-Escribano MF, Witte T, Alarcon-Riquelme ME, Martin J (2007) Association of a CD24 gene polymorphism with susceptibility to systemic lupus erythematosus. Arthritis Rheum 56:3080–3086

    Article  CAS  PubMed  Google Scholar 

  59. Wang L, Lin S, Rammohan KW, Liu Z, Liu JQ, Liu RH, Guinther N, Lima J, Zhou Q, Wang T, Zheng X, Birmingham DJ, Rovin BH, Hebert LA, Wu Y, Lynn DJ, Cooke G, Yu CY, Zheng P, Liu Y (2007) A dinucleotide deletion in CD24 confers protection against autoimmune diseases. PLoS Genet 3:e49

    Article  PubMed  PubMed Central  Google Scholar 

  60. Kristensen BO, Andersen PL (1978) Autoantibodies in untreated and treated essential hypertension. I. Acta Med Scand 203:55–59

    Article  CAS  PubMed  Google Scholar 

  61. Cui H, Wang YM, Kuang YZ (1992) Association between essential hypertension and immunology. Zhonghua Nei Ke Za Zhi 31:21–23, 60

    CAS  PubMed  Google Scholar 

  62. Ishizaka N, Aizawa T, Ohno M, Usui Si S, Mori I, Tang SS, Ingelfinger JR, Kimura S, Nagai R (2002) Regulation and localization of HSP70 and HSP25 in the kidney of rats undergoing long-term administration of angiotensin II. Hypertension 39:122–128

    Article  CAS  PubMed  Google Scholar 

  63. Bravo J, Quiroz Y, Pons H, Parra G, Herrera-Acosta J, Johnson RJ, Rodriguez-Iturbe B (2003) Vimentin and heat shock protein expression are induced in the kidney by angiotensin and by nitric oxide inhibition. Kidney Int Suppl:S46-51

  64. Parra G, Quiroz Y, Salazar J, Bravo Y, Pons H, Chavez M, Johnson RJ, Rodriguez-Iturbe B (2008) Experimental induction of salt-sensitive hypertension is associated with lymphocyte proliferative response to HSP70. Kidney Int Suppl:S55-59

  65. Pockley AG, De Faire U, Kiessling R, Lemne C, Thulin T, Frostegard J (2002) Circulating heat shock protein and heat shock protein antibody levels in established hypertension. J Hypertens 20:1815–1820

    Article  CAS  PubMed  Google Scholar 

  66. Mao H, Li Z, Zhou Y, Zhuang S, An X, Zhang B, Chen W, Nie J, Wang Z, Borkan SC, Wang Y, Yu X (2008) HSP72 attenuates renal tubular cell apoptosis and interstitial fibrosis in obstructive nephropathy. Am J Physiol Renal Physiol 295:F202–214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Schmitt E, Gehrmann M, Brunet M, Multhoff G, Garrido C (2007) Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy. J Leukoc Biol 81:15–27

    Article  CAS  PubMed  Google Scholar 

  68. Lin YP, Hsu ME, Chiou YY, Hsu HY, Tsai HC, Peng YJ, Lu CY, Pan CY, Yu WC, Chen CH, Chi CW, Lin CH (2010) Comparative proteomic analysis of rat aorta in a subtotal nephrectomy model. Proteomics 10:2429–2443

    Article  CAS  PubMed  Google Scholar 

  69. Musial K, Szprynger K, Szczepanska M, Zwolinska D (2010) The heat shock protein profile in children with chronic kidney disease. Perit Dial Int 30:227–232

    Article  CAS  PubMed  Google Scholar 

  70. Marzec L, Zdrojewski Z, Liberek T, Bryl E, Chmielewski M, Witkowski JM, Rutkowski B (2009) Expression of Hsp72 protein in chronic kidney disease patients. Scand J Urol Nephrol 43:400–408

    Article  CAS  Google Scholar 

  71. Endemann M, Bergmeister H, Bidmon B, Boehm M, Csaicsich D, Malaga-Dieguez L, Arbeiter K, Regele H, Herkner K, Aufricht C (2007) Evidence for HSP-mediated cytoskeletal stabilization in mesothelial cells during acute experimental peritoneal dialysis. Am J Physiol Renal Physiol 292:F47–56

    Article  CAS  PubMed  Google Scholar 

  72. Bender TO, Bohm M, Kratochwill K, Lederhuber H, Endemann M, Bidmon B, Aufricht C (2010) HSP-mediated cytoprotection of mesothelial cells in experimental acute peritoneal dialysis. Perit Dial Int 30:294–299

    Article  CAS  PubMed  Google Scholar 

  73. Mueller T, Bidmon B, Pichler P, Arbeiter K, Ruffingshofer D, VanWhy SK, Aufricht C (2003) Urinary heat shock protein-72 excretion in clinical and experimental renal ischemia. Pediatr Nephrol 18:97–99

    PubMed  Google Scholar 

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  1. Pediatrics, Nephrology, Medical College of Wisconsin, 999 N. 92nd St., Suite C510, Milwaukee, WI, 53226, USA

    Rajasree Sreedharan & Scott K. Van Why

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Sreedharan, R., Van Why, S.K. Heat shock proteins in the kidney. Pediatr Nephrol 31, 1561–1570 (2016). https://doi.org/10.1007/s00467-015-3297-x

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