Hypertensive Nephropathy

The kidneys are involved in the regulation of blood pressure through the secretion of renin [40]. Therefore, the kidney is not only one of the important target organs for hypertension damage but also the organ that causes hypertension. Hypertensive nephropathy is the second leading cause of the end-stage renal disease after DN. The prevalence of hypertensive nephropathy is increasing, and 20% of hypertensive patients develop renal insufficiency. Renal vascular hypertension is a syndrome in which renal vascular injury leads to decreased renal perfusion, causing arterial hypertension. Hypertension can affect every renal compartment, including vascular, glomerular, and podocyte injury. In recent years, some evidence suggests that hypertension also damages tubular cells, such as tubular interstitial fibrosis and epithelial-to-mesenchymal transition (EMT) [41]. However, clinical treatment of hypertensive nephropathy is relatively limited, mainly using antihypertensive drugs to protect residual nephrons and delay the progression of renal damage. Numerous studies have explored the pathogenesis of hypertensive nephropathy in terms of the renin-angiotensin system, oxidative stress, endothelial dysfunction, inflammatory response, and genetic factors. However, the specific pathogenesis of hypertensive nephropathy is still poorly understood.

In recent years, several studies have shown that DUSPs are also involved in the pathogenesis of hypertensive nephropathy. Chen et al. identified 267 genes, including DUSP1/ MKP1, as differentially expressed genes associated with hypertensive nephropathy by analyzing microarray data of GSE99325 and GSE32591 in Gene Expression Omnibus. DUSP1/MKP1 downregulation was further confirmed in an angiotensin II [42] treated HK-2 cell model. In VSMCs cells, angiotensin (Ang)-(1-7) counteracts the effects induced by Ang II overproduction mainly by regulating MKP1 activity [43]. This finding suggests that DUSP1/MKP1 may be involved in the progression of hypertensive nephropathy.DUSP5 belongs to nuclear MKPs and can be induced by heat shock proteins and growth factors in mammalian cells.ERK1/2 is the main substrate of DUSP5 and can be dephosphorylated by its phosphatase activity, while a decrease in DUSP5 can in turn enhance the magnitude and duration of ERK signaling [ 44,45].

In contrast, ERK can maintain DUSP5 stability by inhibiting the ubiquitination of DUSP5, which is independent of ERK kinase activity but dependent on ERK-DUSP5 interaction. Zhang et al. [46] found that renal injury in hypertensive KO rats, including renal blood flow, proteinuria, glomerular injury, and renal fibrosis, was significantly improved. Notably, most DUSPs KO animals exhibited a worsening phenotype in the disease model, but the KO of DUSP5 was nephroprotective. This may be related to the cell type of DUSPs members and their substrate preference. In VSMCs, activated ERK1/2 and PKC promote calcium inward flow and promote vasoconstriction [47]. In DUSP5 KO mice, DOCA -salt-induced hypertension is followed by enhanced myogenic responsiveness of afferent small arteries and anterior glomerular arteries and improved self-regulation of renal blood flow, accompanied by reduced MCP-1 expression and reduced macrophage infiltration, as well as reduced transforming growth factor-β (TGF-β1), MMP2 and MMP9 expression in the kidney. Thus, the KO of DUSP5 has a protective effect against hypertension-induced kidney injury. The roles and mechanisms of other DUSP members in hypertensive nephropathy need to be further investigated.

Click here to get Cistanche extract

Diabetic Nephrology

Diabetic nephropathy is the leading cause of end-stage renal disease and is a common microvascular complication of diabetes mellitus. Clinical management of DN is much more problematic than other renal diseases due to complex metabolic disorders, and therapeutic options to prevent progressive loss of renal function are rare. The etiology of DN is more complex than expected. In addition to genetic factors, high glucose, glycosylation products, renal hemodynamics, and cytokines are associated with DN and signaling pathway disorders. activation of MAPK signaling pathways, especially p38 and JNK MAPK, is closely associated with the development of DN [29-33]. An increasing number of studies have shown that p38 MAPK is highly activated in glomeruli of DN mice or DN patients, and inhibition of the p38 MAPK pathway has beneficial effects on the development of DN by suppressing the increase in fibronectin expression and apoptosis. Although the detailed molecular mechanisms by which MAPKs are activated in DN models have not been fully elucidated, DUSPs, as specific inhibitors of MAPKs, have been shown to play an important role in MAPK-mediated DN pathogenesis, as evidenced by the following findings.

First, the deregulation of DUSP has been observed in various DN models.DUSP1/MKP1 is the first identified and most extensively studied member of the family of DUSPs. It is expressed in a variety of tissues and cells and is involved in a variety of biological events such as cell death, cancer, inflammation, and metabolic diseases. Reduced expression of DUSP1/MKP1 was detected in the kidney of STZ-mediated diabetic mice, which contributes to the development of diabetes [20]. Furthermore, in thylakoid cells and tubular epithelial cells, high glucose treatment resulted in a significant reduction in DUSP1/MKP1 expression, which is consistent with the in vivo findings. Similarly, reductions in DUSP4/MKP2, DUSP6/ mkkp3, and DUSP10/MKP5 were observed in the diabetic kidneys of STZ-treated mice [34]. For atypical DUSPs, only DUSP26 was studied in DN mice. Huang et al [35] found that DUSP26 expression was downregulated in renal tissues of DN patients and mouse models.DUSP26-KO mice were worse biomarkers of DN than streptozotocin-treated WT mice. All these studies clearly indicate that DUSPs are downregulated in DN models, suggesting a pathogenic pathological role in DN.

Second, functional analysis of DUSPs showed that the reduction of DUSPs contributes to the activation of MAPKs in DN. Since the activation of MAPKs is common in DN, it is not surprising to find reduced expression of DUSPs. However, their substrates may be different. In renal thylakoid cells, DUSP1/MKP1 is preferred to the JNK pathway, which is an upstream activator of Mff phosphorylation [36]. In tubular epithelial cells, overexpression of DUSP1/ MKP1 improved hg-induced expression levels of type I collagen, type IV collagen, and fibronectin by inactivating the p38 and ERK1/2 pathways [37,38]. However, in another study, the authors demonstrated that the M2 macrophage-derived exosome miR-25-3p could improve hg-induced podocyte injury by activating autophagy, and DUSP1/MKP1 was shown to be a downstream target and mediated the inhibition of hg-induced podocyte injury by exosome miR-25-3p [39]. The different roles of DUSP1/MKP1 may be cell-type related. In cultured podocytes and glomeruli, diabetes-induced reduction of DUSP4 enhanced p38 and JNK activity, while overexpression of DUSP4 prevented p38 and JNK activation. However, DUSP26 inhibition enhanced the activation of all three major types of MAPKs in podocytes [35]. These studies show the substrate preference of individual DUSPs members.

Third, genetic alterations of DUSPs can regulate the progression of DN. To observe the role of DUSPs in DN, transgenic and knockout (KO) mice of DUSPs were prepared. Currently, most of the DUSPs family members with gene deletions are available for functional analysis. Mice with full deletion of DUSPs are fertile, for example, DUSP1/MKP1, DUSP4, DUSP22, and DUSP26-KO mice have been tested in DN models. Consistent with their down-regulation of expression, KO mice exhibit an accelerated progression of DN as evidenced by the development of proteinuria and the promotion of glomerulosclerosis. In contrast, transgenic mice exhibited the opposite effect. For example, DUSP1/MKP1 overexpression reduces glomerular apoptosis in high glucose-induced DUSP1/MKP1 transgenic mice [36]. However, studies involving DN patients are very limited.

In summary, DUSPs have an important pathological role in DN. downregulation of DUSPs contributes to the activation of MAPKs. Since overexpression of DUSPs is beneficial for DN animals, pharmacological activation of DUSPs may be an option for translational medicine.

Herbal Cistanche

Acute Kidney Injury

AKI is a common and serious clinical syndrome characterized by a rapid decline in renal function. AKI has received a lot of attention in recent years due to its clinical significance, such as organ failure and poor prognosis.AKI can be caused by both ischemic and pharmacological injury. The ultimate renal injury depends not only on the direct effect of the injury but also on the adverse reaction of the renal tissue. In the last decades, great efforts have been made to elucidate the role of inflammation and cytokines, and many genes or important players involved in AKI have been identified. However, the pathophysiological mechanisms of AKI have not been fully elucidated. activation of MAPK is associated with AKI-induced apoptosis, suggesting that MAPK inhibition contributes to the attenuation of AKI. For example, cisplatin increases renal injury by upregulating p38 and JNK [48]. Thus, DUSPs are thought to play a role in AKI because they are specific phosphatases for MAPKs.

In a cisplatin-induced mouse model, DUSP1/MKP1 expression was downregulated by cisplatin, which may be a new possible mechanism for MAPK (JNK and p38) phosphorylation in cisplatin-induced renal injury [49]. The authors suggested that modulation of MKP1 expression may be a novel approach to ameliorate cisplatin-induced renal injury. Similarly, reduced DUSP7 and increased phosphorylated ERK were observed in endothelial cells of septic AKI mice, and treatment with antisense oligonucleotides of miR-107 restored DUSP7 expression, inhibited ERK phosphorylation, and reduced secretion of necrosis factor-α in septic AKI mice [24]. For atypical DUSPs, Xu et al [50] showed that DUSP14 expression was reduced in an ischemia-reperfusion (IR) rat model and that upregulation of DUSP14 attenuated IR-induced oxidative stress and inflammatory responses by enhancing NF- 2 and deactivating the NF-κB pathway. However, the unexpected upregulation of DUSP1/MKP1 observed in a rat model of AKI using DNA microarrays contradicts other findings [51]. To date, the role of other DUSP members in AKI has not been explored. In conclusion, these studies provide new clues to the mechanism of action of DUSPs in AKI and the potential treatment of AKI.

Standardized Cistanche

Chronic Kidney Disease

With increasing morbidity and mortality, CKD is becoming a global public health challenge that imposes a heavy burden on patients and society. Renal inflammation and interstitial fibrosis are the prevalent pathological manifestations of CKD progression. At the molecular level, many growth factors and cytokines are involved in this process, leading to the differentiation of renal interstitial fibroblasts into an activated myofibroblast phenotype. In addition, chronic inflammation, oxidative stress, and abnormal metabolism also contribute to CKD. notably, EMT is one of the relevant mechanisms of interstitial fibrosis and TGF-β1 plays a key role in the progression of EMT [52].

In patients with CKD, all three MAP kinase pathways are activated, and pharmacological or genetic strategies to block MAPKs inhibit renal fibrosis in various animal models [53,54].DUSPs, as negative regulators of MAPKs, should play a role in CKD. Li et al [55] found that in a rat model of unilateral ureteral obstruction and in a TGF-β1-treated Overexpression of DUSP4 attenuates TGF-β1-induced EMT by inhibiting the JNK signaling pathway, whereas low expression of DUSP4 promotes TGF-β1-induced EMT by enhancing JNK phosphorylation. this finding suggests that DUSP4 acts as a negative regulator of TGF-β1 induction through a junk-dependent In glomerular thylakoid cells, treatment with connective tissue growth factor activates these cells to produce extracellular matrix (ECM). Wahab et al.[56] found that connective tissue growth factor promotes the survival of activated thylakoid cells by upregulating DUSP1/MKP1, suggesting that connective tissue growth factor has a pro-fibrotic effect in thylakoid cells. However, CKD is a complex pathophysiological change involving apoptosis, inflammation, and TGF-β1/Smad pathway. Therefore, the roles and mechanisms of DUSP members in CKD need to be further investigated.

Lupus Nephritis

LN is a common manifestation of systemic lupus erythematosus (SLE) causing renal damage and is the second leading cause of secondary glomerulonephritis in China [57]. The pathological classification of LN is mainly based on glomerular inflammation. Several studies have suggested the involvement of DUSPs in LN. as previously described, abnormal expression of DUSPs can be found in patients with LN. Tse-Hua et al. found that DUSP22 protein levels were significantly lower in peripheral blood T cells of SLE patients and negatively correlated with SLE disease activity index and antidsDNA antibody levels. Furthermore, in LN patients [58], the downregulation of DUSP22 in T cells was highly correlated with daily urinary protein volume and poor renal prognosis. Therefore, the authors concluded that the downregulation of DUSP22 in T cells is a novel biomarker for the diagnosis and prognosis of SLE nephritis. In contrast, elevated levels of DUSP23 mRNA were found in CD4+ T cells of SLE patients, although no association was found between DUSP23 mRNA expression and typical serological and clinical parameters associated with SLE [59]. Furthermore, DNA methylation and histone modifications have been associated with gene regulation in immune cells [23,60]. This is similar to the abnormal DNA methylation of CD4+ t cells in patients with IgA nephropathy [61]. lN can be defined as an autoimmune disease. An increasing number of studies have shown that DUSPs are involved in autoimmune diseases (e.g., DUSP2, DUSP7, DUSP10, and DUSP12) or t-cell activation (e.g., DUSP1/MKP1, DUSP5, and DUSP14) [62-64]. Thus, additional members of DUSPs will be found to play a role in the pathogenesis of LN.

Cistanche supplements

Conclusions

DUSPs have received a lot of attention as a type of tyrosine, serine/threonine bispecific phosphatase. Previous studies on DUSPs have focused on cancer research. Recently, DUSPs have been shown to be associated with many important cellular processes. There is growing evidence that DUSPs have important physiological and pathological functions not only in normal conditions but also in renal diseases.DUSPs are key regulators of DN, AKI, hypertensive nephropathy, and renal fibrosis. However, the gene expression and precise functions of DUSPs in the human kidneys are poorly understood and need to be elucidated in the future. However, understanding the roles and regulatory mechanisms of DUSP members in renal diseases will help to provide new ideas for the prevention and treatment of renal diseases. the DUSPs family will be a new target in the field of renal diseases.

Why can herbal Cistanche extract benefit the kidneys?

The ancient description of Cistanche's efficacy is summarized as Tonifying kidney Yang, nourishing jinxed, and taking a light body for a long time. Cistanche mainly acts on the kidney organs.

In western medical theory, the main function of the kidney is the filter of the human body, metabolizing harmful substances in the human body through physical means. It is associated with kidney failure, nephritis, kidney cancer, low testosterone production, and so on. In short, damages the kidney organs. The mechanism of Cistanche treating these diseases can be summarized as follows: 1. Strong antioxidant capacity and inhibition of renal cell apoptosis. 2. The ability to promote cell proliferation and the recolonization of kidney cells. The most antioxidant of the four commonly cited active ingredients is lineside.

REFERENCES

40. Seccia TM, Caroccia B, Calò LA. Hypertensive nephropathy. Moving from classic to emerging pathogenetic mechanisms. J Hypertens. 2017 Feb;35(2):205–12.

41. Rodrigues-Díez R, Carvajal-González G, Sánchez-López E, Rodríguez-Vita J, Rodrigues Díez R, Selgas R, et al. Pharmacological modulation of epithelial-mesenchymal transition caused by angiotensin II. Role of ROCK and MAPK pathways. Pharm Res. 2008 Oct; 25(10):2447–61.

42. Chen X, Cao Y, Wang Z, Zhang D, Tang W. Bioinformatic analysis reveals novel hub genes and pathways associated with hypertensive nephropathy. Nephrology. 2019 Nov; 24(11):1103–14.

43. Sousa-Lopes A, de Freitas RA, Carneiro FS, Nunes KP, Allahdadi KJ, Webb RC, et al. Angiotensin (1-7) inhibits Ang II-mediated ERK1/2 activation by stimulating MKP-1 activation in vascular smooth muscle cells. Int J Mol Cell Med. 2020;9(1):50–61.

44. Kucharska A, Rushworth LK, Staples C, Morrice NA, Keyse SM. Regulation of the inducible nuclear dual-specificity phosphatase DUSP5 by ERK MAPK. Cell Signal. 2009 Dec; 21(12):1794–805.

45. Kidger AM, Rushworth LK, Stellzig J, Davidson J, Bryant CJ, Bayley C, et al. Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling. Proc Natl Acad Sci U S A. 2017 Jan 17;114(3): E317–e26.

46. Zhang C, He X, Murphy SR, Zhang H, Wang S, Ge Y, et al. Knockout of dual-specificity protein phosphatase 5 protects against hypertension-induced renal injury. J Pharmacol Exp Ther. 2019 Aug;370(2):206–17.

47. Earley S, Brayden JE. Transient receptor potential channels in the vasculature. Physiol Rev. 2015 Apr;95(2):645–90.

48. Thongnuanjan P, Soodvilai S, Chatsudthipong V, Soodvilai S. Fenofibrate reduces cisplatin-induced apoptosis of renal proximal tubular cells via inhibition of JNK and p38 pathways. J Toxicol Sci. 2016;41(3):339–49.

49. Jung YJ, Park W, Kang KP, Kim W. SIRT2 is involved in the cisplatin-induced acute kidney injury through regulation of mitogen-activated protein kinase phosphatase-1. Nephrol Dial Transplant. 2020 Jul 1;35(7):1145–56.

50. Xu J, Ma L, Fu P. Eriocitrin attenuates ischemia reperfusion-induced oxidative stress and inflammation in rats with acute kidney injury by regulating the dual-specificity phosphatase 14 (DUSP14)-mediated Nrf2 and nuclear factor-κB (NF-κB) pathways. Ann Transl Med. 2021 Feb;9(4):350.

51. Chang NJ, Weng WH, Chang KH, Liu EK, Chuang CK, Luo CC, et al. Genome-wide gene expression profiling of ischemia-reperfusion injury in rat kidney, intestine, and skeletal muscle implicates a common involvement of MAPK signaling pathway. Mol Med Rep. 2015 May;11(5):3786–93.

52. Stambe C, Nikolic-Paterson DJ, Hill PA, Dowling J, Atkins RC. p38 Mitogen-activated protein kinase activation and cell localization in human glomerulonephritis: correlation with renal injury. J Am Soc Nephrol. 2004 Feb;15(2):326–36.

53. Stambe C, Atkins RC, Tesch GH, Masaki T, Schreiner GF, Nikolic-Paterson DJ. The role of p38alpha mitogen-activated protein kinase activation in renal fibrosis. J Am Soc Nephrol. 2004 Feb;15(2):370–9.

54. Ma FY, Flanc RS, Tesch GH, Han Y, Atkins RC, Bennett BL, et al. A pathogenic role for c-Jun amino-terminal kinase signaling in renal fibrosis and tubular cell apoptosis. J Am Soc Nephrol. 2007 Feb;18(2):472–84.

55. Li Z, Liu X, Tian F, Li J, Wang Q, Gu C. MKP2 inhibits TGF-β1-induced epithelial-to-mesenchymal transition in renal tubular epithelial cells through a JNK-dependent pathway. Clin Sci. 2018 Nov 13;132(21):2339–55.

56. Wahab N, Cox D, Witherden A, Mason RM. Connective tissue growth factor (CTGF) promotes activated mesangial cell survival via up-regulation of mitogen-activated protein kinase phosphatase-1 (MKP-1). Biochem J. 2007 Aug 15;406(1):131–8.DUSPs and Kidney Diseases 25 Kidney Dis 2022;8:13–25.

57. Hou JH, Zhu HX, Zhou ML, Le WB, Zeng CH, Liang SS, et al. Changes in the spectrum of kidney diseases: an analysis of 40,759 biopsy-proven cases from 2003 to 2014 in China. Kidney Dis. 2018 Feb;4(1):10–9.

58. Chuang HC, Chen YM, Hung WT, Li JP, Chen DY, Lan JL, et al. Downregulation of the phosphatase JKAP/DUSP22 in T cells as a potential new biomarker of systemic lupus erythematosus nephritis. Oncotarget. 2016 Sep 6; 7(36):57593–605.

59. Balada E, Felip L, Ordi-Ros J, Vilardell-Tarrés M. DUSP23 is over-expressed and linked to the expression of DNMTs in CD4(+) T cells from systemic lupus erythematosus patients. Clin Exp Immunol. 2017 Feb;187(2):242–50.

60. Jeong Y, Du R, Zhu X, Yin S, Wang J, Cui H, et al. Histone deacetylase isoforms regulate innate immune responses by deacetylating mitogen-activated protein kinase phosphatase-1. J Leukoc Biol. 2014 Apr;95(4):651–9.

61. Sallustio F, Serino G, Cox SN, Dalla Gassa A, Curci C, De Palma G, et al. Aberrantly methylated DNA regions lead to low activation of CD4+ T-cells in IgA nephropathy. Clin Sci. 2016 May;130(9):733–46.

62. Huang CY, Lin YC, Hsiao WY, Liao FH, Huang PY, Tan TH. DUSP4 deficiency enhances CD25 expression and CD4+ T-cell proliferation without impeding T-cell development. Eur J Immunol. 2012 Feb;42(2):476– 88.

63. Lu D, Liu L, Ji X, Gao Y, Chen X, Liu Y, et al. The phosphatase DUSP2 controls the activity of the transcription activator STAT3 and regulates TH17 differentiation. Nat Immunol. 2015 Dec;16(12):1263–73.

64. Chuang HC, Tan TH. MAP4K family kinases and DUSP family phosphatases in T-cell signaling and systemic lupus erythematosus. Cells. 2019 Nov 13;8(11):1433.

From Haiyang Li; Jiachuan Xiong; Yu Du; Yinghui Huang; Jinghong Zhao.

Department of Nephrology, The Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, PR China