Journal of Receptors and Signal Transduction

ISSN: 1079-9893 (Print) 1532-4281 (Online) Journal homepage: http://www.tandfonline.com/loi/irst20

Leptin and chronic kidney diseases

Song Mao, Li Fang, Fen Liu, Siqiong Jiang, Liangxia Wu & Jianhua Zhang

To cite this article: Song Mao, Li Fang, Fen Liu, Siqiong Jiang, Liangxia Wu & Jianhua Zhang
(2018): Leptin and chronic kidney diseases, Journal of Receptors and Signal Transduction, DOI:
10.1080/10799893.2018.1431278

To link to this article: https://doi.org/10.1080/10799893.2018.1431278

Published online: 01 Feb 2018.

Submit your article to this journal

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=irst20
JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION, 2018
https://doi.org/10.1080/10799893.2018.1431278

REVIEW ARTICLE

Leptin and chronic kidney diseases

Song Maoa, Li Fanga, Fen Liua, Siqiong Jianga, Liangxia Wua and Jianhua Zhangb
a
Department of Pediatrics, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China; bDepartment of Pediatrics,
Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

ABSTRACT ARTICLE HISTORY

Chronic kidney diseases (CKD), a common outcome of various kidney diseases, cause a series of refrac- Received 7 September 2017
tory complications, which lead to great economic burdens on patients. The clinical outcomes of CKD Revised 14 January 2018
depend on various factors, including metabolic disorders. Leptin, a peptide hormone, produced in adi- Accepted 16 January 2018
pose tissues, plays an important role in regulating food consumption and energy expenditure. Leptin
KEYWORDS
also influences the immune system and hematopoiesis. Increased leptin status is observed in CKD, lep- Chronic kidney diseases;
tin deficiency attenuates the immune response in nephritis. Conversely, leptin inhibits the development leptin; prognosis
of obesity, which is closely associated glomerular disorder. Now, the precise role of leptin in CKD
remains elusive. This review will give an integrated understanding of the potential role of leptin and
its interactions with other signal molecules in CKD.

1. Introduction
Chronic kidney diseases (CKD) are a common clinical out-
come of almost all the glomerular diseases [1]. A number of
CKD cases progress to end-stage renal diseases (ESRD), which
often requires long-term dialysis or even renal transplant-
ation. Due to the high prevalence and harms of CKD, early
intervention and monitoring is imperative for CKD therapy.
On the other hand, CKD is likely to be complicated with
some severe disorders, such as cardiovascular and metabolic
diseases [2], which result in increased morbidity and mortal-
ity. Hence, identification of signaling molecules involved in
the development of CKD and its complications is of signifi-
cant importance.
Leptin, a messenger protein, is secreted from adipocytes
and exerts effects in cellular mechanisms, particularly meta-
bolic signaling pathways [3]. Leptin plays an important role in
the nutrition, energy balance, immune regulation and inflam-
mation [4], which are closely associated with the risk and pro-
gress of glomerular diseases. Overexpression of leptin can
induce the production of type I collagen [5]. Leptin in the body
is mainly cleared by kidney [6]. The decreased glomerular filtra-
tion rate in CKD may cause the increase of leptin status. On the
other hand, leptin also induces oxidative stress and endothelial
dysfunction [7], which may result in cardiovascular disorders,
an important complication of CKD. Hence, leptin may be a
potential therapeutic target in CKD. Due to the multiple effects
of leptin on CKD, an in-depth and comprehensive view of the
role of leptin and its associated signaling molecules on CKD is
of significant importance.
In the past decades, a number of investigations and
reviews have been performed to study the association
between leptin and the risk and progression of CKD [8–10].
However, the integrated study of the relationship between
leptin and CKD was rare. With the accumulated evidence, we,
therefore, wrote this review to yield an updated understand-
ing of the association between CKD and leptin, as well as the
signaling pathways of leptin and the role of the possible
interactions between leptin and its associated molecules
in CKD.
2. Leptin
Leptin, a 167-amino acid protein, secreted mainly by adipo-
cytes, regulates energy metabolism and induces different
outcomes in various tissues of human body. Leptin exerts
effects on food intake, coagulation processes, angiogenesis,
insulin-related functions and vascular remodeling [11], which
are involved in the pathogenesis of cardiovascular diseases
and dyslipidemia. Leptin also promotes the metastasis of
cancers [12]. Besides the regulation of energy balance
and nutriton, leptin also functions as a proinflammatory
molecule [13].
Leptin is mainly cleared by the kidney through glomerular
filtration and metabolic degradation in renal tubules.
Increased status of leptin may indicate poor kidney function.
Administration of leptin is likely to lead to higher blood pres-
sure and proteinuria [14]. Leptin also plays an important role
in systemic inflammatory response [15], which can promote
the progression of glomerular diseases. Positive association
was also observed between leptin status and cardiovascular
injury parameters, such as arterial rigidity and atherosclerosis
[16], which often occur in the late stage of glomerular

CONTACT Siqiong Jiang Jsqmmail@sina.cn; Liangxia Wu wlxmed@sina.com Department of Pediatrics, Shanghai Jiao Tong University Affiliated Sixth
People’s Hospital, Shanghai China; Jianhua Zhang zjh12195@sina.com Department of Pediatrics, Xinhua Hospital, Shanghai Jiao Tong University School of
Medicine, Shanghai, China
These authors contributed equally to this study.
ß 2018 Informa UK Limited, trading as Taylor & Francis Group
2 S. MAO ET AL.
MFN2, Sam68, HSP90,
PI3K-C2a, CRP, PKA
insulin
Leptin
hypertension
vascular
proliferation
PI3K
cardiac
disorder
AKT-ATF2
IL-18
Figure 1. Signaling pathways for leptin regulation.
diseases. Leptin status is positively associated with endothe-
lial dysfunction [17], which is an indicator of cardiovascular
disorders. Leptin also promotes oxidative stress [18], which
contributes to the kidney injury.
Based on the above-mentioned evidence, leptin is a risk
factor for the onset and progression of glomerular diseases.
3. Leptin signaling pathways
In the past, a lot of studies have been conducted to focus on
the signaling pathways of leptin. The putative physiological
and pathological role of leptin depends partly on its signal-
ing pathways. Leptin expression is regulated by various sig-
naling molecules and leptin also modulates the expression of
lots of genes. Additionally, the interaction between leptin
and other proteins may influence the role of leptin in the
glomerular diseases. Figure 1 shows a diagram of the differ-
ent signaling pathways that have been reported to be linked
to the regulation of leptin.
Leptin acts upon neuronal system controlling gonado-
tropin releasing hormone [19]. Increased status of leptin
plays a role in the development of hypoganodism [20], which
is likely to occur in the late stage of glomerular diseases.
Leptin exerts effects in adventitial pericyte growth, survival,
migration and promotion of endothelial network formation
[21]. The vascular proliferation contributes to the onset of
cardiovascular disorders, which is a common complication of
glomerular diseases and exacerbate its prognosis. Leptin pro-
motes the secretion of IL-6 in osteoarthritis patients [22].
Leptin promotes IL-18 expression in breast cancer cells via
the PI3K/AKT-ATF2 signaling pathway [23]. Inflammation and
infection are commonly observed in glomerular diseases [24].
GATA2
PPARγ
oxidative
stress
neuronal system
hypoganodism ROS
IL-6,matrix
metalloproteinases,
megalin,Wnt,bone
density, JAK/STAT3
Overexpression of leptin may increase the risk of kidney dis-
eases by promoting inflammation. Leptin status was closely
associated with hypertension [25], which is a common symp-
tom of glomerular diseases, particularly in serious kidney
injury. Leptin promotes metastatic potential and stemness in
breast cancer via TGF-b1 pathway [26], which can lead to the
renal fibrosis. Leptin promotes osteoblast differentiation of
human aortic VICS in an Akt and ERK dependent manner
[27]. Leptin inhibited peroxisome-proliferator activated recep-
tor c (PPARc) expression through GATA binding protein 2
(GATA2) binding to a site around -2323 in PPARc1 promoter
[28]. PPARc1 can inhibit the oxidative stress, reduce the ROS.
Downregulation of PPARc1 expression of hepatic stellate cells
plays a role in the pathogenesis of liver fibrosis [29]. Leptin
enhances the expression and secretion of certain matrix met-
alloproteinases in human gingival fibroblasts [30]. Leptin
inhibits megalin expression and activates cell signaling path-
ways that upregulates fibrotic protein expression [31]. Wnt
signaling plays a role in embryogenesis and tumorigenesis,
including the regulation of cell proliferation, survival and dif-
ferentiation [32]. Wnt pathway in the hypothalamus is regu-
lated by diet and leptin [33]. Bone density and bone mineral
content are regulated by leptin acting via the sympathetic
nervous system [34]. Administration of leptin increased the
duration of hypothalamic JAK/STAT3 signaling [35].
High levels of leptin in circulation and leptin receptor muta-
tion are associated with prostate cancer risk in human
patients [36].
On the other hand, a number of signaling molecules also
regulates the expression of leptin. MFN2 mutations lead to
mitochondrial dysfunction, upper body adipose hyperplasia
and inhibition of leptin expression [37]. Mitochondrial

Leptin
oxidative inflammation
stress lipids disorder
CKD
Figure 2. The potential mechanism of the role of leptin in CKD.
dysfunction decreases the energy production. Decrease of
leptin status may be a compensatory mechanism. Sam68
mediates the regulation of leptin signaling in breast cancer
cells, regulating the cell survival, proliferation and growth
[38]. Heat shock protein 90 (HSP90) is a molecular chaperone
involving in regulating cellular homeostasis [39]. HSP90 inhib-
ition attenuated leptin-induced JAK2 and STAT3 signaling,
modulating leptin signal transduction [40]. Class I phosphino-
sitide 3-kinases (PI3Ks) are important positive regulators of
metabolism [41]. Inhibition of PI3K-C2a induces leptin resist-
ance [42]. C-reactive protein (CRP) hinders the access of lep-
tin to the central nervous system, and elevation of human
CRP within the CNS has a negative impact on the physio-
logical actions of leptin [43]. Protein kinase A (PKA) modu-
lates leptin sensitivity and adiposity [35]. PKA contributes to
renal fibrosis [44], the characteristic of CKD.
In a word, leptin is a metabolic regulator. It keeps the
homeostasis of energy production. Leptin interacts with
many signaling molecules to play a role in the regulation of
inflammation, oxidative stress and proliferation. High level of
leptin is closely associated with poor renal function. Leptin
might be a therapeutic target of glomerular diseases.
4. Leptin and CKD
The relationship between leptin and CKD has attracted the
attention of researchers. A number of studies have indicated
that leptin is involved in the susceptibility and progression of
CKD. Leptin promotes the oxidative stress, inflammation and
lipids disorder, which contribute to the risk of CKD. The mul-
tiple functions of leptin also affect the prognosis and compli-
cations of CKD. For example, hypogonadism is a common
endocrine disorder in men with CKD, adiposity and leptin
contributes to the deficiency of testosterone, which leads to
the susceptibility to hypogonadism [45]. Cardiovascular
JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION 3
endothelial nutritonal testosterone
dysfunction status bone
disorder
events are the common complications, and the leading
causes of morbidity and mortality of CKD [46]. Leptin pro-
motes the vascular proliferations, which contributes to the
cardiovascular disorders in CKD. On the other hand, leptin
increases platelet aggregation and promotes endothelial dys-
function [47], which plays an important role in the develop-
ment of atherothrombosis. A positive association between
leptin and IL-6 was observed [48], and LPS injection caused
an increase of serum leptin status [49]. Leptin was also asso-
ciated with inflammatory-associated cachexia [50]. Leptin
may promote the infection and inflammation, which contrib-
ute to the risk and progression of CKD. Leptin may be
involved in the development of insulin resistance and glu-
cose disorder, which are more prevalent as renal function
deteriorates. CKD patients are often complicated with mineral
and bone disorders, particularly during hemodialysis. Leptin
is produced by osteoblasts and influences the bone and lip-
ids metabolism.
Based on the above-mentioned data, it is reasonable to
speculate that leptin may play a role in the development of
CKD, increased level of leptin may predict a poor prognosis.
Several facts may account for our speculations. First, leptin is
mainly cleared by the kidney, poor kidney function indicates
the accumulation of leptin. Increased level of leptin promotes
the reactive oxygen species (ROS) production, which is
involved in the pathogenesis of CKD [51]. Inflammation and
lipids disorder are also induced by the overexpression of lep-
tin. Second, leptin induces the endothelial dysfunction and
vascular proliferation, which contributes to the cardiovascular
events in CKD [52]. Finally, CKD, particularly the late stage of
CKD, is closely associated with protein-energy wasting, which
is a state of decreased body stores of protein and energy
fuels, and leads to increased morbidity and mortality. Leptin
inhibits appetite and increases energy expenditure, which
contributes to the exacerbation of nutritional status, and
4 S. MAO ET AL.
even leading to anorexia and malnutrition in CKD patients,
particularly maintenance hemodialysis cases [53]. Hence, lep-
tin is also regarded as an important cause of uremic
cachexia.
In addition to the adverse effects of leptin on CKD, we
should pay more attention to the inhibitory effects of leptin
in obesity, which is a double-edge sword. Obesity itself
increases the burden on the kidneys and is a risk factor for
kidney injury [54]. Also, obesity contributes to the metabolic
disorders [55], which are closely associated with the progres-
sion of glomerular diseases. In this sense, due to the inhibi-
tory effects on obesity, leptin may protect against the renal
injury. Experimental studies showed that leptin decreased
caloric intake and glucose levels in diabetic rats [56]. Therapy
of leptin and pioglitazone attenuates the pathologic changes
of brain in transgenic Alzheimer’s disease mouse [57].
Notably, metreleptin, a recombinant methionyl human leptin,
reduces body weight and daily insulin dose in type 1 dia-
betes mellitus [58]. Metreleptin exerts therapeutic effects in
lipodystrophy [59], which indicated that leptin is likely to be
applied in metabolic disorders. Future clinical trials regarding
the role of leptin in glomerular diseases are needed. On the
other hand, CKD, particularly hemodialysis patients are asso-
ciated with malnutrition, or even cachexia, which aggravates
the prognosis of CKD. Leptin decreases the appetite and
increases the energy expenditure, resulting in the worsening
of nutritional status. In this sense, the role of leptin in CKD
depends partly on the nutritional and metabolic state. If the
patient is with a high body mass index, an appropriate
higher leptin status may be helpful. Identification of the
exact role of leptin in CKD calls for more animal and human
studies.
Leptin exerts effects in the intrinsic glomerular cells.
Leptin downregulation decreased the production of IL-23 in
podocytes [60]. Leptin also inhibited the expression of podo-
cyte-associated molecules including nephrin, podocin, podo-
planin and podocalyxin [61]. Leptin induced the expression
of matrix metalloproteinases (MMPs) in glomerular mesangial
cells [62]. Leptin stimulated the proliferation of transforming
growth factor-beta 1 (TGF-b1) in glomerular endothelial cells
[5]. Based on the above-mentioned evidence, leptin plays a
role in various glomerular cells, leading to the symptoms of
renal injury, such as proteinuria and renal fibrosis. Further
studies should be conducted to clarify its detailed
pathogenesis.
In a word, leptin may be a therapeutic target of CKD.
Meanwhile, the role of leptin in energy metabolism indicates
that the nutritional status should be considered in the moni-
toring of the status of leptin. Here, we present the potential
role of leptin in CKD (Figure 2).
5. Conclusion and future directions
Taken together, leptin may be a therapeutic target of CKD.
The alteration of leptin status in CKD provides new insight
to the treatment or severity of CKD. The precise mechanism
of the role of leptin in CKD needs to be further clarified, par-
ticularly the molecules along the signaling pathways of
leptin. Meanwhile, persistent raise of leptin levels may lead
to anorexia, or even cachexia. Hence, it may be more appro-
priate to target leptin in CKD with a close monitoring of
nutritional status.
Future generation of leptin / mice or mice overexpress-
ing leptin gene will promote the understanding of the role
of leptin in the development and progression of CKD and
discover the novel functions of leptin. Human clinical trials
will yield a more deepening understanding of the effects of
leptin in CKD. Based on the researches, leptin is an potential
therapeutic target and biomarker of CKD prognosis.
Disclosure statement
There is no conflict of interest for all authors.
Funding
This study was supported by Grant from the National Natural Science
Foundation of China [grant number 81600578].
References
[1] Cobrin AR, Blois SL, Kruth SA, et al. Biomarkers in the assessment
of acute and chronic kidney diseases in the dog and cat. J Small
Anim Pract. 2013;54:647–655.
[2] Safder O, Al sharif S, Kari JA. Pediatric CKD and cardiovascular dis-
ease. Cadiovasc Hematol Disord Drug Target. 2014;14:177–184.
[3] Koltes DA, Spurlock ME, Spurlock DM. Adipose triglyceride lipase
protein abundance and translocation to the lipid droplet increase
during leptin-induced lipolysis in bovine adipocytes. Domest
Anim Endocrinol. 2017;61:62–76.
[4] La Cava A, Matarese G, Ebling FM, et al. Leptin-based immune
intervention: current status and future directions. Curr Opin
Investig Drugs. 2003;4:1327–1332.
[5] Han DC, Isono M, Chen S, et al. Leptin stimulates type I collagen
production in db/db mesangial cells: glucose uptake and TGF-
beta type II receptor expression. Kidney Int. 2001;59:1315–1323.
[6] Cumin F, Baum HP, de Gasparo M, et al. Removal of endogenous
leptin from the circulation by the kidney. Int J Obes Relat Metab
Disord. 1997;21:495–504.
[7] Teixeira TM, da Costa DC, Resende AC, et al. Activation of Nrf2-
antioxidant signaling by 1,25-dihydroxycholecalciferol prevents
leptin-induced oxidative stress and inflammation in human endo-
thelial cells. J Nutr. 2017;147:506–513.
[8] Wolf G, Chen S, Han DC, et al. Leptin and renal disease. Am J
Kidney Dis. 2002;39:1–11.
[9] Zhang J, Wang N. Leptin in chronic kidney disease: a link
between hematopoiesis, bone metabolism, and nutrition. Int Urol
Nephrol. 2014;46:1169–1174.
[10] Tsujimoto Y, Shoji T, Tabata T, et al. Leptin in peritoneal dialysate
from continuous ambulatory peritoneal dialysis patients. Am J
Kidney Dis. 1999;34:832–838.
[11] Harwood HJ Jr. The adipocyte as an endocrine organ in the regu-
lation of metabolic homeostasis. Neuropharmacology. 2012;63:
57–75.
[12] Zou H, Liu Y, Wei D, et al. Leptin promotes proliferation and
metastasis of human gallbladder cancer through OB-Rb leptin
receptor. Int J Oncol. 2016;49:197–206.
[13] Koleva D, Orbetzova MM, Nikolova JG, et al. Pathophysiological
role of adiponectin, leptin and asymmetric dimethylarginine in
the process of atherosclerosis. Folia Med (Plovdiv). 2016;58:
234–240.
[14] Ibrahim HS, Froemming GR, Omar E, et al. ACE2 activation by
xanthenone prevents leptin-induced increases in blood pressure

and proteinuria during pregnancy in Sprague-Dawley rats. Reprod
Toxicol. 2014;49:155–161.
[15] Sviri S, Neuman T, Berry EM, et al. Leptin levels and clinical out-
comes in patients with systemic inflammatory response syn-
drome. Anaesth Intensive Care. 2016;44:124–125.
[16] Liberale L, Bonaventura A, Vecchi
e A, et al. The role of adipo-
cytokines in coronary atherosclerosis. Curr Atheroscler Rep.
2017;19:10.
[17] Ortiz Segura MDC, Del Rıo Navarro BE, Rodrıguez Espino BA, et al.
Abnormality of adipokines and endothelial dysfunction in
Mexican obese adolescents with insulin resistance. Endocr Res.
2017;42:252–259.
[18] Fr€ uhbeck G, Catalan V, Rodrıguez A, et al. Involvement of the lep-
tin-adiponectin axis in inflammation and oxidative stress in the
metabolic syndrome. Sci Rep. 2017;7:6619.
[19] Quennell JH, Mulligan AC, Tups A, et al. Leptin indirectly regu-
lates gonadotropin-releasing hormone neuronal function.
Endocrinology. 2009;150:2805–2812.
[20] Cobo G, Cordeiro AC, Amparo FC, et al. Visceral adipose tissue
and leptin hyperproduction are associated with hypogonadism in
men with chronic kidney disease. J Ren Nutr. 2017;27:243–248.
[21] Riu F, Slater SC, Garcia EJ, et al. The adipokine leptin modulates
adventitial pericyte functions by autocrine and paracrine signal-
ling. Sci Rep. 2017;7:5443.
[22] Pearson MJ, Herndler-Brandstetter D, Tariq MA, et al. IL-6 secre-
tion in osteoarthritis patients is mediated by chondrocyte- syn-
ovial fibroblast cross-talk and is enhanced by obesity. Sci Rep.
2017;7:3451.
[23] Li K, Wei L, Huang Y, et al. Leptin promotes breast cancer cell
migration and invasion via IL-18 expression and secretion. Int J
Oncol. 2016;48:2479–2487.
[24] Yilmaz G, Sevinc C, Ustundag S, et al. The relationship between
mean platelet volume and neutrophil/lymphocyte ratio with
inflammation and proteinuria in chronic kidney disease. Saudi J
Kidney Dis Transpl. 2017;28:90–94.
[25] JeR dzura A, Adamczyk P, Bjanid O, et al. Non-dipping status and
selected adipokines concentration in children with primary arter-
ial hypertension. Clin Exp Hypertens. 2017;39:718–725.
[26] Miller JA, Lang JE, Ley M, et al. Human breast tissue disposition
and bioactivity of limonene in women with early-stage breast
cancer. Cancer Prev Res (Phila). 2013;6:577–584.
[27] Rosa M, Paris C, Sottejeau Y, et al. Leptin induces osteoblast dif-
ferentiation of human valvular interstitial cells via the Akt and
ERK pathways. Acta Diabetol. 2017;54:551–560.
[28] Zhou Q, Guan W, Qiao H, et al. GATA binding protein 2 mediates
leptin inhibition of PPARc1 expression in hepatic stellate cells
and contributes to hepatic stellate cell activation. Biochim
Biophys Acta. 2014;1842:2367–2377.
[29] Guan W, Cheng F, Wu H, et al. GATA binding protein 3 is corre-
lated with leptin regulation of PPARc1 in hepatic stellate cells.
J Cell Mol Med. 2017;21:568–578.
[30] Williams RC, Skelton AJ, Todryk SM, et al. Leptin and pro-inflam-
matory stimuli synergistically upregulate MMP-1 and MMP-3
secretion in human gingival fibroblasts. PLoS One. 2016;11:
e0148024.
[31] Briffa JF, Grinfeld E, Poronnik P, et al. Uptake of leptin and albu-
min via separate pathways in proximal tubule cells. Int J Biochem
Cell Biol. 2016;79:194–198.
[32] Helfer G, Tups A. Hypothalamic Wnt signalling and its role in
energy balance regulation. J Neuroendocrinol. 2016;28:12368.
[33] Benzler J, Andrews ZB, Pracht C, et al. Hypothalamic WNT signal-
ling is impaired during obesity and reinstated by leptin treatment
in male mice. Endocrinology. 2013;154:4737–4745.
[34] Qasem RJ, Li J, Tang HM, et al. Maternal protein restriction during
pregnancy and lactation alters central leptin signalling, increases
food intake, and decreases bone mass in 1 year old rat offspring.
Clin Exp Pharmacol Physiol. 2016;43:494–502.
[35] Yang L, McKnight GS. Hypothalamic PKA regulates leptin sensitiv-
ity and adiposity. Nat Commun. 2015;6:8237.
JOURNAL OF RECEPTORS AND SIGNAL TRANSDUCTION 5
[36] Alshaker H, Sacco K, Alfraidi A, et al. Leptin signalling, obesity
and prostate cancer: molecular and clinical perspective on the
old dilemma. Oncotarget. 2015;6:35556–35563.
[37] Rocha N, Bulger DA, Frontini A, et al. Human biallelic MFN2 muta-
tions induce mitochondrial dysfunction, upper body adipose
hyperplasia, and suppression of leptin expression. Elife. 2017;
6:e23813.
[38] Perez-Perez A, Sanchez-Jimenez F, Vilarin
~o-Garcıa T, et al. Sam68
mediates the activation of insulin and leptin signalling in breast
cancer cells. PLoS One. 2016;11:e0158218.
[39] Kuan YC, Hashidume T, Shibata T, et al. Heat shock protein 90
modulates lipid homeostasis by regulating the stability and func-
tion of sterol regulatory element-binding protein (SREBP) and
SREBP cleavage-activating protein. J Biol Chem. 2017;292:
3016–3028.
[40] Hosoi T, Kohda T, Matsuzaki S, et al. Key role of heat shock pro-
tein 90 in leptin-induced STAT3 activation and feeding regulation.
Br J Pharmacol. 2016;173:2434–2445.
[41] Vadas O, Burke JE, Zhang X, et al. Structural basis for activation
and inhibition of class I phosphoinositide 3-kinases. Sci Signal.
2011;4:re2.
[42] Alliouachene S, Bilanges B, Chaussade C, et al. Inactivation of
class II PI3K-C2a induces leptin resistance, age-dependent insulin
resistance and obesity in male mice. Diabetologia. 2016;59:
1503–1512.
[43] Li J, Wei D, McCrory MA, et al. Human C-reactive protein impedes
entry of leptin into the CNS and attenuates its physiological
actions in the CNS. Biochem J. 2016;473:1215–1224.
[44] Guo YS, Yuan WJ, Zhang AP, et al. Parathyroid hormone-mitogen-
activated protein kinase axis exerts fibrogenic effect of connective
tissue growth factor on human renal proximal tubular cells. Chin
Med J (Engl). 2010;123:3671–3676.
[45] Fugl-Meyer KS, Nilsson M, Hylander B, et al. Sexual function and
testosterone level in men with conservatively treated chronic kid-
ney disease. Am J Mens Health. 2017;11:1069–1076.
[46] Malhotra R, Nguyen HA, Benavente O, et al. Association between
more intensive vs less intensive blood pressure lowering and risk
of mortality in chronic kidney disease stages 3 to 5: a systematic
review and meta-analysis. JAMA Intern Med. 2017;177:1498–1505.
[47] Considine RV. Human leptin: an adipocyte hormone with weight-
regulatory and endocrine functions. Semin Vasc Med. 2005;5:
15–24.
[48] Graszmann S, Wirsching J, Eichelmann F, et al. Association
between peripheral adipokines and inflammation markers: a sys-
tematic review and meta-analysis. Obesity (Silver Spring).
2017;25:1776–1785.
[49] Pohl J, Woodside B, Luheshi GN. Leptin modulates the late fever
response to LPS in diet-induced obese animals. Brain Behav
Immun. 2014;42:41–47.
[50] Demiray G, Deg  irmenciog lu S, Ug
urlu E, et al. Effects of serum
leptin and resistin levels on cancer cachexia in patients with
advanced-stage non-small cell lung cancer. Clin Med Insights
Oncol. 2017;11:1179554917690144.
[51] Ren Y, Du C, Shi Y, et al. The Sirt1 activator, SRT1720, attenuates
renal fibrosis by inhibiting CTGF and oxidative stress. Int J Mol
Med. 2017;39:1317–1324.
[52] Mitsides N, Cornelis T, Broers NJH, et al. Extracellular overhydra-
tion linked with endothelial dysfunction in the context of inflam-
mation in haemodialysis dependent chronic kidney disease. PLoS
One. 2017;12:e0183281.
[53] Yadav VK, Oury F, Suda N, et al. A serotonin-dependent mechan-
ism explains the leptin regulation of bone mass, appetite, and
energy expenditure. Cell. 2009;138:976–989.
[54] Fang Q, Wang L, Yang D, et al. Blockade of myeloid differenti-
ation protein 2 prevents obesity-induced inflammation and
nephropathy. J Cell Mol Med. 2017;21:3776–3786.
[55] Choi MS, Park HJ, Kim SR, et al. Long-term dietary supplementa-
tion with yerba mate ameliorates diet-induced obesity and meta-
bolic disorders in mice by regulating energy expenditure and
lipid metabolism. J Med Food. 2017;20:1168–1175.
6 S. MAO ET AL.
[56] da Silva AA, Hall JE, do Carmo JM. Leptin reverses hyperglycemia
and hyperphagia in insulin deficient diabetic rats by pituitary-
independent central nervous system actions. PLoS One.
2017;12:e0184805.
[57] Fernandez-Martos CM, Atkinson RAK, Chuah MI, et al. Combination
treatment with leptin and pioglitazone in a mouse model of
Alzheimer's disease. Alzheimers Dement (NY). 2016;3:92–106.
[58] Vasandani C, Clark GO, Adams-Huet B, et al. Efficacy and safety of
metreleptin therapy in patients with type 1 diabetes: a pilot
study. Diabetes Care. 2017;40:694–697.
[59] Brown RJ, Meehan CA, Cochran E, et al. Effects of metreleptin in
pediatric patients with lipodystrophy. J Clin Endocrinol Metab.
2017;102:1511–1519.
[60] Goto K, Kaneko Y, Sato Y, et al. Leptin deficiency down-regulates
IL-23 production in glomerular podocytes resulting in an attenu-
ated immune response in nephrotoxic serum nephritis. Int
Immunol. 2016;28:197–208.
[61] Liu BL, Chen YP, Cheng H, et al. The protective effects of
curcumin on obesity-related glomerulopathy are associated
with inhibition of Wnt/b-catenin signaling activation in podo-
cytes. Evid Based Complement Alternat Med. 2015;2015:
827472.
[62] Lee MP, Madani S, Sekula D, et al. Leptin increases expression
and activity of matrix metalloproteinase-2 and does not alter col-
lagen production in rat glomerular mesangial cells. Endocr Res.
2005;31:27–37.