Heat shock proteins and kidney disease: perspectives of HSP therapy

Abstract

Heat shock proteins (HSPs) mediate a diverse range of cellular functions, prominently including folding and regulatory processes of cellular repair. A major property of these remarkable proteins, dependent on intracellular or extracellular location, is their capacity for immunoregulation that optimizes immune activity while avoiding hyperactivated inflammation. In this review, recent investigations are described, which examine roles of HSPs in protection of kidney tissue from various traumatic influences and demonstrate their potential for clinical management of nephritic disease. The HSP70 class is particularly attractive in this respect due to its multiple protective effects. The review also summarizes current understanding of HSP bioactivity in the pathophysiology of various kidney diseases, including acute kidney injury, diabetic nephropathy, chronic glomerulonephritis, and lupus nephritis-along with other promising strategies for their remediation, such as DNA vaccination.

Keywords: DNA vaccines; Kidney diseases; Molecular chaperones; T cell regulation; Tissue protection.

Fig. 1

Expression of HSPs in various parts of kidney

Fig. 2

The role of Hsp70 in signal transduction pathways. a Role of Hsp70 in signal transduction pathways of NF-κB. Intracellular HSP70 may also involve in preserving I-κB complex by interacting with IKK (Uchinami et al. 2002). HSP70 forms a complex with IκBα, attenuating NF-κB activity. HSP70 might bind IκBα to prevent its phosphorylation by IκB kinase, or HSP70 might inhibit IκB kinase directly, thereby inhibiting the degradation of I-κB and the subsequent activation of the NF-κB pathway (Shimizu et al. 2002). NF-κB activation induced by various stimuli is mediated by members of the TNF receptor-associated factor (TRAF) adapter family (le Luong et al. 2013). Intracellular HSP70 was demonstrated to inhibit NF-κB activation by binding TRAF6 via the TRAF-C domain and preventing its ubiquitination, thus resulting in inhibition of inflammatory mediator production (Cao et al. 1996). b Role of Hsp70 in signal transduction pathways of TGF signaling. HSP70 inhibits TGF-β signal by Smad-dependent and Smad-independent pathways. Upon TGFβ stimulation, Smad2 and Smad3 are phosphorylated by the activated TGFβ type I receptor kinase, forming a stable complex with Smad 4 in cytoplasm and then accumulating in the nucleus to regulate transcription of target genes. Moreover, in renal cells, TGF-beta direct or via TRAF6 stimulates rapid phosphorylation of the TGF-beta-activated kinase (TAK)1 and TAK1-binding protein, in turn activating MKK, which appears to function upstream of JNK and p38 (Schnaper et al. 2009 ). In contrast, Smad7 inhibits the TGFβ receptor type I-dependent Smad2/3 activation. Intracellular HSP70 interrupting Smad2/3 protein phosphorylation and its nuclear translocation and accumulation increases Smad7 protein expression, binds TRAF6, and reduces the phosphorylation of JNK and p38 MAPK, providing a protective effect (Zhou et al. 2010). c Role of Hsp70 in stress kinases (MAPK) signal transduction. The relative extent of MAPK activities, including JNK, p38, and ERK, has been proposed to determine cell fate after injury. Hsp70 downregulates also the activation of stress kinases (JNK and p38), and suppresses activation of caspases in renal cells (Suzuki et al. 2005) The activity of the MEK/ERK pathway that is upregulated by HSP70 may be relevant to renal protection. HSP70 provides most of the protective effects by activation of Raf, MEK, and ERK phosphorylation and cell survival (Wang et al. , Park et al. 2002). Abbreviations: TGF-β transforming growth factor beta, MAPK mitogen-activated protein kinase, JNK c-Jun N-terminal kinase, ERK extracellular signal-regulated kinases, MEK MKK–mitogen-activated protein kinase kinase, MKKK mitogen-activated protein kinase kinase kinase, Raf a family of serine/threonine-specific protein kinases

Fig. 3

Role of Hsp70 in immune inflammation. HSP70-induced beneficial protective effect is caused not only by intracellular produced HSP70 but also by HSP70 in immune cells and subsequent regulatory function toward anti-inflammation in immune and non-immune renal diseases. Extracellular Hsp70 binds with the Toll-like receptors (TLR) 2 and 4 on the antigen-presenting cells (APCs): dendritic cells (СD11c), monocytes/macrophages, and tubular cells in site of inflammation or injury. Other transmembrane receptors such as CD91 and LOX-1 may be the receptors for HSP 70. APCs present HSP 70 epitopes with help of MHC-II to HSP-specific CD4+ T cells, ultimately leading to expansion of СD4+CD25+ (T regulatory cells) with subsequent anti-inflammatory or immunomodulatory effect via IL-10 and TGF-β production (Kim et al. 2014). Moreover, HSP70 may directly bind to the TLR2/4 of CD4+ T cells, and activate the expansion of Tregs. HSP70 may also converse inflammatory macrophage (M1) phenotype to the anti-inflammatory (M2) macrophage providing the resolution of inflammation. TCR T cell receptor, MHC-II major histocompatibility complex class II

Fig. 4

Interplay of HSP70, HSP 90, and HSP60 in renal cells. The unfolded or misfolded (client) protein is initially recognized by the Hsp70/40 system with CHIP (carboxy-terminus of Hps70 interacting protein) and, subsequently, transferred to HSP90. CHIP is a Ubox E3 ubiquitin ligase that associates with Hsp70 or Hsp90 via its TPR domain and ubiquitinates misfolded substrates (Murata et al. 2003). HSP90 forms a multicomponent complex with cochaperones including Hsp40, Hsp70, HOP (Hsp70 and Hsp90 organizing protein), and p23 that serve to recognize client proteins and assist their binding to the Hsp90 heteroprotein complex (Dickey et al. ,Hernández et al. 2002). Subsequently, the cochaperone p23 interacts with the Hsp70/40-HOP-Hsp90-substrate complex resulting in the release of Hsp70/40 and HOP. The folded protein, HSP90, and cochaperone p23 released from the complex and could be participated in the next cycle of protein folding action (Wang et al. 2014). HSP70, HSP40, and TCP-1 ring complex (TRiC) also form a high molecular mass complex that mediates protein folding in ATF-dependent process. HSP70 and HSP 40 bind first to the nascent chain and subsequently mediated the interaction of the growing polypeptide with the TRiC cylinder. As translation proceeds, ATF-dependent folding of an N-terminal domain of the client protein occurs within the central cavity of the TRiC cylinder, while the C-terminal regions remain associated with HSP70/HSP40 in an unfolded conformation (Frydman et al. 1994)