Oxidative stress, a common molecular pathway for kidney disease: Role of the redox enzyme p66Shc

Abstract

Accumulation of oxidative stress is considered to be a causative mediator of kidney disease, and oxidative stress can affect some key regulators of kidney homeostasis and control a number of signaling pathways that are relevant to kidney disease. The p66Shc adaptor protein was discovered more than two decades ago as a pivotal regulator of oxidative stress. Given the importance of oxidative stress in kidney homeostasis, several molecular and cellular studies using a p66Shc antagonist have depicted a role for p66Shc in renal pathophysiology. The specificity of p66Shc functions may depend upon their intracellular localization and expression in the kidney. This review focuses on the biochemical functions of the p66Shc adaptor protein, as well as its potential implications in the pathophysiology of kidney disease. In addition, the concept that pharmacologic modulation of p66Shc expression and activity may serve as a novel and effective target for the treatment of kidney disease is discussed.

• Kidney
• oxidative stress and redox enzyme
• p66Shc
• ROS

Introduction

Kidney disease is a serious but common affliction that adversely affects human health, and increases costs to health care systems worldwide. Its increasing incidence cannot be fully explained by traditional risk factors. Recent research indicates that oxidative stress is prevalent in kidney disease patients, and is considered to be an important pathogenic mechanism.1 In 2006, it was first noted that streptozotocin (STZ)-treated mice carrying a targeted mutation of the p66Shc gene displayed significantly lower levels of renal injury, and increased resistance to oxidative stress.2 This stimulated a large number of studies aimed at defining the pathophysiologic role of p66Shc in kidney disease. Indeed, because reactive oxidative stress (ROS) is an important risk factor, the identification of a novel mediator of ROS-associated changes in renal function could provide effective strategies to fight various renal disorders. The present review primarily focuses on the mechanisms linking the p66Shc adaptor protein to the pathophysiology of various renal disorders. In addition, the pharmacologic modulation of p66Shc expression and its activity in fighting kidney disease are also discussed.

Structure and function of p66Shc

Structure of p66Shc

P66Shc is an adaptor protein that is encoded by a single locus in Drosophila (dShc), and by four loci in mammals – Shc (ShcA), Sli (ShcB), Rai (ShcC), and RalP.3 Three isoforms encoded by the ShcA locus are designated according to their molecular weights as p46Shc, p52Shc, and p66Shc, respectively. The three isoforms share a Src-homology 2 domain, a collagen-homology region, and a phosphotyrosine-binding domain (named SH2-CH1-PTB);4 while p66Shc contains an additional amino-terminal proline-rich region named CH2, which functions as a redox enzyme implicated in generation of mitochondrial ROS and translation of oxidative signals into apoptosis.3,5,6

P66Shc and ROS

ROS are small molecules that are highly reactive because of the presence of unpaired electrons.7 In brief, intracellular ROS levels can be increased through three main mechanisms: an increasing in the activity of oxidases, a reduction in ROS scavenging, and mitochondrial respiratory chain leakage.8 P66Shc has been reported to act through all of these.9 Previous research has shown that the phosphorylated p66Shc promotes activation of small GTPase Rac1 by displacing nucleotide-exchange factor SOS from the Grb2 complex; activated Rac1 then stimulates membrane-bound NADPH oxidase complex formation and ROS generation10 (Figure 1). In addition, p66Shc can reduce the expression of antioxidant enzymes and regulatory factors such as glutathione peroxidase-111 and MnSOD12 by means of down-regulation of forkhead-type transcription factors (e.g., Foxo3a).13

Figure 1. Role of p66Shc in regulation of ROS and apoptosis. Phosphorylated p66Shc (p-p66Shc) stimulates NADPH oxidase complex formation and ROS generation. In addition, p66Shc reduces the expression of antioxidant enzymes (e.g., MnSOD), p-p66Shc is transported into mitochondria, and then p66shc is released from the high -molecular-mass complex that contains TOM, TIM, and mHSP70, the released p66Shc acts as an oxidoreductase and promotes ROS generation, eventually leading to cellular oxidative injury and apoptosis. (see details in the text).

The role of p66Shc in mitochondrial oxidative stress is an area of active investigation. Previous research has indicated that activation of PKCβ can phosphorylate p66Shc at Ser36. Phosphorylated p66Shc thus becomes a target for prolyl isomerase Pin1, which recognizes a proline residue that follows a phosphorylated serine residue. P66Shc is then transported into mitochondria, thereby inducing ROS generation (Figure 1).14 Mitochondria are dynamic organelles that are able to interchange their morphology between an elongated interconnected mitochondrial network and a fragmented discrete phenotype by undergoing the processes of mitochondrial fusion and fission.15,16 Recently, we have investigated the relationship between mitochondrial dynamic changes and ROS overproduction in renal tissue,17 as well as the expression of the adaptor protein p66Shc and mitochondrial shaping proteins in vitro. We find that mitochondrial dynamic alterations may be mediated by p66Shc through its interaction with dynamin-related protein 1, which may serve as an upstream trigger of mitochondrial ROS overproduction; these then results in tubular oxidative injury under hyperglycemic conditions (unpublished).

P66Shc and apoptosis

Recent results show that p66Shc regulates the mitochondrial apoptotic pathway.18 P66Shc is a part of the multi-subunit complex comprising TIM, TOM, and mHSP70 in mitochondria under normal conditions.9 Oxidative stress causes p66Shc to dissociate from this complex. Released p66Shc then acts as an oxidoreductase and transfers electrons from reduced cyt C to oxygen. The incomplete reduction of oxygen results in ROS production, and this promotes the formation of a mitochondrial permeability transition pore (mPTP),19,20 resulting in an increase in mitochondrial membrane permeability to ions, solutes and water. This is followed by swelling and disruption of the organelle, with consequent release of proapoptotic factors into the cytosol and caspase activation, eventually leading to cellular apoptosis5 (Figure 1).

P66Shc and signal transduction

The association of Shc adaptor protein family members in tyrosine phosphorylation signaling pathways is well recognized.21,22 The notion that Shc adaptor proteins activate tyrosine phosphorylation signaling suggests their plausible role in growth regulation, including metastasis and carcinogenesis. Recent data indicate that a novel molecular mechanism exists in some steroid-stimulated cancers, whereby redox signaling induced by p66Shc mediates steroid action via a non-genomic pathway.23 In addition, research performed by Bashir et al. intriguingly find a regulatory pathway operated by p66Shc that involves Eps8 and Rac1 proteins as downstream targets in esophageal cancer,24 suggesting that p66Shc plays a role in the regulation of carcinomas, and represents a possible mechanism of signaling for the development of squamous cell carcinoma and adenocarcinoma.

Role of p66Shc in kidney disease

The kidney is a highly energetic organ that relies heavily on aerobic metabolism for the production of ATP. During the pathogenesis of kidney disease, perturbations in cellular oxidant handling influence downstream cellular signaling and promote renal cell senescence, apoptosis, and even necrosis; and eventually lead to a loss of cell function and, ultimately, to disease.1,18 New and reliable markers of circulating oxidative stress have become available in kidney disease patients, and these have confirmed the long-held belief that in kidney disease the organ is in a state of oxidative stress.25,26 Studies have indicated that the main ROS in kidney disease are superoxide (), the hydroxyl radical (OH⁻) and hydrogen peroxide (H₂O₂); and the main contributing sites of ROS generation in renal cells include the mitochondria, endoplasmic reticulum, peroxisomes, and lysosomes.18 Many intracellular molecules and enzymes are involved in this process, and NADPH oxidase has been identified as the major enzyme of generation.27 While recent studies have shown that the adaptor protein p66Shc is another important regulatory factor of oxidative stress in kidney, p66Shc also seems to interfere with the regulation of cellular mechanisms intimately involved in the manifestation of kidney disease, such as diabetic kidney disease (DKD), renal ischemia-reperfusion (IR) injury, and renal interstitial fibrosis. Although the differential expression of p66Shc has been demonstrated in aging kidneys,28 the functional significance of p66Shc in the pathogenesis of kidney disease still requires further investigation.

P66Shc and diabetic kidney disease

There is a significant body of literature that indicates that oxidative stress is a common link among the major pathways involved in the development and progression of DKD.29,30 Previous studies by our laboratory found that high glucose and angiotensin II (Ang II) led to an increased expression of total and phosphorylated-p66Shc in proximal tubular cells.31 These changes were accompanied by increased production of mitochondrial ROS, and ultimately reduced cellular survival31 (Figure 2).

Figure 2. Role of p66Shc in renal tubular cells. Phosphorylated p66Shc(p-p66Shc) increases mitochondrially mediated oxidative stress in tubular epithelial cells, and promotes cellular apoptosis; thus ameliorating renal ischemia/reperfusion injury, tobacco-related kidney injury, and diabetic kidney disease; and also enhancing nephrotoxicity. In addition, p-p66Shc could aggravate renal ischemia/reperfusion injury and cisplatin-induced nephrotoxicity via diverse pathways as indicated in the figure. At times, p-p66Shc can also modulate cellular EMT and the expression of ECM. Overall, it appears that activation of p66Shc accelerates the progression of various kidney diseases (see details in the text).

The role of p66Shc as a mediator of oxidative damage in DKD is further supported by in-vivo evidence. Menini et al.2 demonstrated that STZ-treated diabetic p66Shc^−/− mice manifested significantly lower levels of proteinuria and had a lower glomerular sclerosis index, compared to wild-type diabetic mice. In agreement with a role for p66Shc in oxidative stress, increased apoptosis was detected in glomerular cells from diabetic wild type mice, but not in diabetic p66Shc^−/− mice, supporting the concept that p66Shc is a major player in mediating stress-induced apoptosis in vivo.2 In line with these aforementioned observations, Menini et al.32 found that p66Shc participates in the pathogenesis of AGE-dependent diabetic glomerulopathy by mediating AGE-induced tissue injury; and that further AGE formation through ROS-dependent mechanisms (after ablation of the gene encoding p66Shc), could protect mice from AGE-induced glomerulopathy by preventing oxidant-dependent tissue injury.

Clinical research further supports p66Shc as a mediator of oxidative damage in DKD. Pagnin et al.33 assessed p66Shc gene expression in peripheral blood mononuclear cells from type 2 diabetic patients and healthy subjects. They found that the level of p66Shc mRNA was significantly higher in type 2 diabetic patients compared with controls, and that this upregulation in expression was significantly associated with plasma isoprostanes, an established in vivo marker of oxidative stress. These studies suggested that diabetic oxidative stress was related to a high level of p66Shc gene expression. A recent study performed by Bock et al.34 demonstrates that activated protein C(aPC) epigenetically suppresses glucose-induced p66Shc expression by enhancing methylation while diminishing acetylation of the p66Shc promoter, using both a rat model of DKD and glucose-stressed podocytes. The suppression of glucose-induced p66Shc expression paralleled the aPC-mediated reduction of glucose-induced mitochondrial p66Shc translocation and ROS generation. These interesting data established that DKD could be ameliorated by epigenetically constraining expression of p66Shc.34

P66Shc in renal ischemia/reperfusion injury

Renal IR injury frequently occurs in patients with acute renal failure.35 It is also an important contributing factor to chronic allograft dysfunction following renal transplantation.36 Using an in-vivo model of renal I/R injury, an excess in ROS and free radicals37 (including H₂O₂), are formed and these are postulated to play a crucial role in the pathogenesis of renal injury.37 Previous studies have shown that the entire EGFR/Ras/MEK/ERK pathway plays an important pro-survival role in the kidney during ischemic renal injury.38–41 However, toxic stress conditions uncouple the activated EGFR from ERK42 and induce necrosis of the proximal tubules during ischemic kidney injury.43,44

The Shc adaptor proteins have been shown to bind to a variety of receptors, including growth factor receptors such as EGFR, and to couple these receptors to Ras activation.45 Investigators have demonstrated that tyrosine-phosphorylated p46Shc and p52Shc isoforms couple activated EGFR to Ras/ERK activation during oxidative stress.46 However, stress conditions (H₂O₂) may also lead to Ser36 phosphorylation of the p66Shc,47 and this functions as a dominant-negative regulator of p46/52Shc, terminating Ras/ERK activation.48–50 The function of p66Shc in renal I/R injury was illustrated by several studies. Arany et al. demonstrated that activated p66Shc inhibited the survival signaling pathway in ischemic renal injury by disconnecting the activated EGFR from Ras/ERK activation, and that this was dependent upon the extent of oxidative stress.51 Recently, Arany et al.52 found that p66Shc/mitochondrial/cyt-c interaction induced oxidative stress and played a pivotal role in tubular injury in the post-ischemic kidney (Figure 2). Thus, manipulating p66Shc might offer a new therapeutic modality to ameliorate renal ischemic injury.

P66Shc in HIV-associated nephropathy

Glomerular visceral epithelial cells or podocytes are highly specialized cells that play a pivotal role in the pathogenesis of human immunodeficiency virus-associated nephropathy (HIV-AN).53 Compelling evidence53,54supports a key role for HIV-1 gene products in podocyte injury that leads to a breach in the integrity of the glomerular filtration barrier and the massive proteinuria that characterizes HIV-AN. The absence of podocyte regeneration after cell injury is a major limitation to the development of effective therapeutic strategies to prevent HIV-AN. Interventions that increase the resistance of this terminally differentiated cell to death signals, then, may offer a novel therapeutic approach to HIV-AN.

The potent stress response regulator Foxo3A is a downstream target of p66Shc redox signals.45,55 Recently, Husain et al. have proposed a model in which inhibition of p66Shc redox activity results in the activation of Foxo3A-dependent stress pathways that shifts the phenotype of podocytes expressing HIV-1 genes away from apoptosis and toward cell survival.56 In the study performed by Husain et al., conditionally immortalized, differentiated human podocytes (CIDHPs) were genetically engineered to co-express a truncated HIV-1 construct (NL4-3-GFP) together with mutant-36 p66Shc(mu-36) or isoform-specific p66Shc siRNA (p66-siRNA). The results documented a pivotal role for p66Shc redox activity in the NL4-3/CIDHP stress phenotype that was abrogated by co-transfection with mu-36 or p66Shc-siRNA, in turn increasing the ability of FOXO3a to promote the survival phenotype.56 Collectively, in CIDHP-expressing HIV-1 genes, these authors have identified a pivotal role for p66Shc redox function in the evolutionarily conserved PI3K/Akt/PKB signaling module, which inactivates Foxo3A (Figure 3). It is believed that a gene-based strategy targeting p66Shc may represent an exciting new avenue for therapeutic intervention in HIV-associated nephropathy.

Figure 3. Role of p66Shc in glomerular cells. In glomerular capillary lumen, p66Shc may act as a negative regulator of immune complexes and reduce the development of autoimmune glomerulonephritis. In addition, phosphorylated p66Shc regulates apoptosis of GMC and podocytes via different pathways in diabetic kidney disease, HIV-associated nephropathy and glomerulonephritis. Therefore, if signaling occurs at the level of mediation of downstream events by p66Shc, one would anticipate different outcomes in various glomerular disease processes (see details in the text). Note: Po, podocytes; Me, mesangial cells; Cap, capillary lumen; GN, glomerulonephritis; DKD, diabetic kidney disease; HIV-AN, HIV-associated nephropathy.

P66Shc in tobacco-related kidney injury

The pathologic role of smoking in the development of chronic obstructive pulmonary diseases, cancer, or cardiovascular diseases has been widely accepted. However, its impact on kidney function has only recently been recognized.57,58 Epidemiologic studies conclude that smoking is an important remediable risk factor for the development of proteinuria,59,60 evolution of chronic kidney disease to end-stage renal disease61, and graft failure in renal transplant patients.62

Animal studies have shown that chronic nicotine exposure increased renal oxidative stress by suppressing antioxidant responses in the kidney,63 and that the oxidative stress induced by smoking is an important factor in the pathogenesis of renal vascular and epithelial injury.64 In an interesting paper published in the recent issue of Nephrology Dialysis Transplantation,65 Arany et al. illustrated that chronic nicotine exposure increased serine 36 phosphorylation(S36A) and renal expression of p66Shc. Arany et al. also found that the phosphorylation of p66Shc exacerbated mitochondrially mediated oxidative stress, and promoted cellular injury and apoptosis in cultured proximal tubule cells stimulated with nicotine65 (Figure 2). This article thus unveils a novel mechanism for the development of tobacco-related kidney injury. In addition, it may assist us in elucidating the exact link between nicotine and the occurrence of kidney injury; and targeting this pathway may achieve therapeutic relevance in the prevention or amelioration of tobacco-related kidney injury.

P66Shc in anticancer drug-induced kidney disorders

Anticancer drugs, such as inhibitors of DNA methyltransferases and histone deacetylases, restore activities of genes that are involved in normal cell function in cancer cells;66 however, they also exhibit renal toxicity that limits their effectiveness,67,68 due to increased production of ROS.69 It has been reported that the histone deacetylase inhibitor trichostatin A (TSA) and the DNA methyltransferase inhibitor 5-azacytidine(5-AZA) exacerbates oxidative stress-induced renal injury by increasing mitochondrial ROS production.70 The p66Shc adaptor protein is a known mediator of cellular oxidative stress injury.47 Since both TSA and 5-AZA have been shown to modify the p66Shc gene,71 it is plausible that p66Shc, at least in part, mediates the renal toxicity of these anticancer drugs. Recently, Arany et al. discovered that TSA and 5-AZA treatments elevated the level of p66Shc by inducing the p66Shc promoter in mouse renal proximal tubule cells.72 In addition, these agents also increased mitochondrial and cytochrome c binding of p66Shc. Downregulation of the expression of p66Shc could also attenuate ROS production induced by TSA or 5AZA. These authors propose that additional modalities that intervene with activation of p66Shc might help prevent the renal toxicity caused by such drugs.

Cisplatin (CP) is a widely used agent in the treatment of various human solid tumors, however, it is greatly limited by its nephrotoxicity.73,74 The principal targets of CP in the kidney are the proximal tubules,75 which undergo both necrosis and apoptosis.

Many studies have identified an array of signaling pathways that mediate CP-induced injury and death of the proximal tubules. ERK is one of the mediators of CP-induced apoptosis,76–78 and ERK has been shown to be able to phosphorylate the adaptor protein p66Shc at its serine36 residue,51,55,79 a known mediator of apoptosis, but whose role in CP-mediated cell death is unclear. Recently, Clark et al. found that overexpression of p66Shc exacerbated, while its knockdown or mutation of the serine36 site, reduced CP-induced nephrotoxicity in vitro; and they also demonstrated CP-induced apoptosis through the ERK-p66Shc pathway in renal proximal tubule cells (Figure 2).80 In addition, Arany et al. found that knockdown of p66Shc or overexpression of heat-shock protein-27(HSP27) improved CP-mediated collapse of the actin cytoskeleton in renal proximal tubule cells. Further studies revealed that p66Shc binds HSP27 after treatment with CP, requiring Ser36 phosphorylation of p66Shc, and these authors proposed a novel function for p66Shc-accelerated, CP-dependent disruption of the actin cytoskeleton81 (Figure 2). Therefore, down-regulating the expression of p66Shc may be a potential strategy to reduce nephrotoxicity and consequential renal insufficiency induced by CP in patients undergoing cancer treatment. This was confirmed by the study by Rattanavich et al., where the authors found that cells transfected with p66Shc siRNA induced p66Shc deficiency could be rescued from CP-induced renal tubular cell apoptosis in FVBN/p66Shc^+/− mice.82

P66Shc in renal interstitial fibrosis

Most of the chronic glomerular diseases are characterized by accumulation of extracellular matrix (ECM) proteins, such as collagens, in mesangium and other glomerular regions, as well as in the renal interstitial compartment.83 Various mechanisms responsible for the abnormal accumulation of ECM have been delineated; for example, it has been established that the epithelial–mesenchymal transition (EMT) is a major mechanism of renal tubulointerstitial fibrosis.84,85

Previous studies indicated that the mineralocorticoid aldosterone (Aldo) induced EMT in renal epithelial cells through mitochondrial derived ROS.86,87 Recently, a study performed by Yuan et al. showed that blocking the mineralocorticoid receptor(MR) with eplerenone remarkably inhibited Aldo-induced EMT in HK-2 cells.88 However, it was unclear as to the molecular targets of MR activation. We now appreciate that the adaptor protein p66Shc is a newly recognized mediator of mitochondrial dysfunction. Yuan et al. demonstrated that Aldo induced mitochondrial superoxide production and increased p66Shc expression and phosphorylation. Suppression of endogenous p66Shc by siRNA blocked Aldo-induced mitochondrial superoxide production and EMT, indicating that the Aldo-induced EMT in HK-2 cells was mediated by the phosphorylation of p66Shc88 (Figure 2). Another study performed by Percy et al. indicated that the expression of p66Shc was increased in age-related renal fibrosis, supporting an association between p66Shc and the development of renal interstitial fibrosis.28

P66Shc and glomerulonephritis

The role of p66Shc as a mediator of oxidative stress and apoptosis in some kidney diseases was discussed above; however, a series of recently published accounts indicates that p66Shc regulates renal pathology via other mechanisms. Recent research has uncovered evidence that p66Shc plays an important role in ET-1-derived intracellular signals89 in glomerular mesangial cells (GMC). Foschi et al.90 presented data showing that ET-1 induced MEK/ERK-dependent p66Shc serine phosphorylation and promoted the formation of a p66Shc/14-3-3 protein complex in GMC, while the serine-binding motif containing 14-3-3 protein was shown to be an important anti-apoptotic protein.91 Moreover, ET-1 has been described to inhibit nitric oxide-induced apoptosis in mesangial cells during glomerulonephritis,92 and it could also inhibit apoptosis of vascular smooth muscle cells induced by nitric oxide and serum deprivation via activation of the ERK pathway.93 Therefore, we hypothesize that ET-1-dependent p66Shc/14-3-3 protein association plays a role in the anti-apoptotic effects of ET-1 in GMC during glomerulonephritis (Figure 3).

It is now understood that autoantibodies induced by autoimmune dysfunction can be deposited in the glomerulus, leading to complement fixation and activation; this, then, can result in the initiation of an inflammatory process that eventually results in the development of glomerulonephritis.94 A very interesting study performed by Finetti et al. demonstrated that p66Shc acted as a negative regulator of autoimmune glomerulopathy.95 These authors found that p66Shc^−/− mice developed a lupus-like autoimmune disease characterized by autoantibody production and immune complex deposition in kidney, resulting in autoimmune glomerulonephritis. In the same study, p66Shc^−/− lymphocytes also displayed enhanced proliferation in response to antigen receptor engagement in vitro. These data identified p66Shc as a negative regulator of lymphocyte activation and autoantibody formation, and loss of this protein may result in abrogation of immunologic tolerance and in the development of systemic autoimmune diseases such as autoimmune glomerulonephritis95 (Figure 3).

Therapeutic strategies of inhibition p66Shc in kidney disease

The above discussion strongly suggests that p66Shc-induced oxidative stress has an important pathophysiologic role in patients with renal disease; consequently, therapeutic strategies that inhibit p66Shc could become significant. In this endeavor, it is interesting to note that the silent information regulator1(SIRT1) (an NAD(+)-dependent histone deacetylase that acts as a chromatin-silencing factor), is involved in various nuclear events such as transcription, DNA replication, and DNA repair.96 A recent study showed that SIRT1 could regulate p66Shc expression in a hyperglycemic environment, and overexpression of SIRT1 inhibited high-glucose-induced p66Shc up-regulation in human umbilical vein endothelial cells.97 In addition, resveratrol, a SIRT1 activator, was proven to be efficient in reducing oxidative stress and maintaining mitochondrial function; and this effect was related to inactivation of p66Shc in glucose-treated renal mesangial cells.98 Additionally, in HK-2 cells, Yuan et al. found that resveratrol restored aldosterone -induced mitochondrial dysfunction and EMT by downregulating p66Shc, thereby retarding the development of renal interstitial fibrosis.88 Glucose-induced p66Shc expression was also epigenetically suppressed by an endogenous coagulation protease activated protein C(aPC) by enhancing methylation while simultaneously diminishing acetylation of the p66Shc promoter in a rat model of DKD; the suppression of p66Shc expression was in fact paralleled by aPC-mediated reduction in glucose-induced mitochondrial p66Shc translocation and ROS generation.34 Thus, we can infer that p66Shc merits further investigation as a novel therapeutic target for renal disease. Some agents, such as resveratrol or other p66Shc inhibitors, may be potential drugs that offer hope to patients with kidney disease. Accordingly, the gene-based strategies targeting p66Shc represent an exciting new avenue of therapeutic methods in the kidney.99 However, whether using these strategies (e.g., siRNA) to silence disease-causing genes100 such as p66Shc could be applied clinically remains to be determined. The data discussed herein constitute a small piece of a much larger puzzle. Both experimental studies and clinical research are needed to explore accurately the relationships between p66Shc and kidney function.

Conclusions and future directions

In conclusion, the role of oxidative stress in renal dysfunction is often underestimated in clinical practice, but emerging evidence continues to highlight its strong correlation with kidney disease. The evidence reviewed here alludes to the fact that the p66Shc protein is involved in the control of various renal functions, such as proliferation of glomerular cells and immune complex deposition. Although much work has been carried out in regard to the functional characterization of p66Shc, its cellular functions need to be further expanded and clarified. An increase in our understanding of p66Shc and mitochondria as a cohesive functioning complex would constitute a fertile area of research.

Importantly, recent findings indicate a more general role for p66Shc in regulating cellular mechanisms involved in kidney disease, such as DKD, ischemic kidney injury and renal interstitial fibrosis. Thus, p66Shc proteins may offer an attractive common therapeutic target for various renal disorders. An in-depth analysis of the structure, function, and the mechanism/mechanisms of action of p66Shc in renal tissue will promote the development of new and effective pharmacologic agents. However, the current studies on the functional effects of p66Shc clearly suffer from the lack of p66Shc-specific agonists or inhibitors. Certainly, the development of newer pharmacologic agonists or inhibitors will create new avenues that will promote our understanding of the physiologic and pathologic actions of p66Shc in renal tissues. In addition, pharmacologic modulation of p66Shc expression and activity may then prove effective in fighting kidney disease as well as reduce the incidence of inflammatory and neuroendocrine-immune stimuli in the overloaded kidney.

Declaration of interest

This study was supported by grants from the National Natural Sciences Foundation of China (81270812, 81100541), PhD programs foundation of ministry of Education of China (2011062110012. Furong Scholars Fund from Hunan Province Education Department, the national basic research program of China 973 program No: 2012CB517600(2012CB517601). The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.