mTOR signaling in kidney diseases

Yuan Gui1* and Chunsun Dai2*

1 Department of Nephrology, UConn Health Center, Farmington, CT, 06030,

USA

2 Center for Kidney Disease, 2nd Affiliated Hospital, Nanjing Medical

University, 262 North Zhongshan Road, Nanjing, Jiangsu, China

*To whom correspondence should be addressed:

Yuan Gui, MD/PhD, Department of Nephrology, UConn Health Center,

Farmington, CT, USA. 06030 (01-319-2593074, E-mail: gui@uchc.edu to Yuan

G).

Chunsun Dai, MD/PhD, Center for Kidney Disease, 2nd Affiliated Hospital,

Nanjing Medical University, 262 North Zhongshan Road, Nanjing, Jiangsu, P.R.

China. 210003 (86-25-52636077, E-mail: daichunsun@njmu.edu.cn to Dai C).

Kidney360 Publish Ahead of Print, published on September 3, 2020 as doi:10.34067/KID.0003782020

Copyright 2020 by American Society of Nephrology.

Abstract

The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase,

is crucial in regulating cell growth, metabolism, proliferation and survival. Under

physiologic condition, mTOR signaling maintains podocyte and tubular cell

homeostasis. In acute kidney injury, activation of mTOR signaling in tubular

cells and interstitial fibroblasts promotes renal regeneration and repair.

However, constitutive activation of mTOR signaling in kidneys results in the

initiation and progression of glomerular hypertrophy, interstitial fibrosis,

polycystic kidney disease and renal cell carcinoma. Here, we summarize the

recent studies about mTOR signaling in renal physiology and injury and discuss

the possibility of which as a therapeutic target for kidney diseases.

Introduction

In 1970s, a Streptomyces hygroscopicus was isolated from a Rapa Nui

(Easter Island) soil sample and the antibiotic-compound named as rapamycin

was separated from this bacteria later [1]. A series of subsequent studies

discovered that this compound has anti-fungal, immunosuppressive and

antitumor properties [2]. In the early 1990s, researchers identified TOR1 and

TOR2 as mediators of the toxic effect of rapamycin on yeast. Later the

mammalian target of rapamycin (mTOR) was identified in mammals [3]. Over

the following decades, mTOR inhibitors have been approved for the treatment

of host-rejection, renal-cell carcinoma, and pancreatic cancer.

The mTOR pathway regulates cell growth, proliferation, survival and

metabolism [4]. Dysregulation of mTOR signaling disrupts renal cell

homeostasis and results in kidney diseases, such as acute kidney injury (AKI)

[5, 6], kidney fibrosis [7, 8], glomerular disease [9, 10], polycystic kidney

disease (PKD) [11, 12], and renal cancer [13]. Notably, the efficiency for mTOR

inhibitors (rapamycin and its analogues) has been demonstrated in many types

of kidney disease [14-16]. Here, we will give a brief review of the mTOR

signaling pathway, the pivotal roles of mTOR in kidney diseases, and targeting

mTOR signaling as a therapeutic strategy for kidney disorders.

Architecture and composition of mTOR complexes

The mammalian target of rapamycin (mTOR) is a 289-kDa serine/threonine

protein kinase belonging to the phosphatidylinositol-3-OH kinase (PI3K)-related

protein kinase family that functions as a central regulator of cell growth,

metabolism, proliferation and survival. As a core component, mTOR consists of

two distinct complexes: mTOR complex 1 (mTORC1) and complex 2 (mTORC2)

[4]. (Fig. 1)

mTORC1

MTORC1 is formed by five major components: mTOR, regulatory-associated

protein of mTOR (Raptor), mammalian lethal with Sec13 protein 8 (mLST8),

proline-rich AKT substrate 40 kDa (PRAS40), and DEP-domain-containing

mTOR-interacting protein (Deptor). Among of them, mLST8 stabilizes the

kinase domain of mTOR, but is dispensable for mTORC1 signaling. Raptor is

essential for mTORC1 activity by assembling the complex and recruiting the

substrates of mTORC1 [17]. Both PRAS40, a raptor binding protein, and Deptor

act as endogenous inhibitors for mTOR kinase activity [18].

mTORC2

MTORC2 is formed by mTOR, mLST8, Deptor, rapamycin-insensitive

companion of mTOR (Rictor), mammalian stress-activated protein kinase

interacting protein 1 (mSIN1), and protein associated with rictor 1 or 2

(PROTOR1/2). Among of them, Rictor interacts extensively with mTOR, defines

mTORC2 assembly and its downstream signaling pathway including Akt,

protein kinase C (PKC), and serum- and glucocorticoid-induced kinases 1

(SGK1), as deletion of this protein remarkably reduces mTORC2 activity [19].

Protor1/2 interacts with Rictor as Rictor-binding subunit of mTORC2. In

addition, mSIN1 is necessary for maintaining mTORC2 assembly and its

capacity of phosphorylating Akt/PKB [20]. Like those in mTORC1, mLST8 is

dispensable for maintaining mTORC2 activity, while Deptor negatively

regulates mTORC2 activity [18].

Regulation of mTORC1 signaling

Growth factors

Many growth factor pathways converge on TSC (tuberous sclerosis complex),

a heterodimer comprising TSC1 (also known as hamartin) and TSC2 (also

known as tuberin), through the PI3K-Akt pathway. TSC inhibits mTORC1

signaling by acting as GTPase-activating protein for Rheb (a small GTPase Ras

homolog enriched in Brain) [21]. TSC1/2 is negatively regulated by

phosphoinositide 3 kinase (PI3K)-phosphoinositide-dependent protein kinase 1

(PDK1), which phosphorylates Akt/PKB at threonine 308 to activate mTORC1

signaling. PTEN, a lipid phosphatase and tumor suppressor, inhibits PI3K

signaling by dephosphorylating phosphatidylinositol-3,4,5-triphosphate (PIP3)

in plasma membrane [22]. Besides PI3K-Akt signaling axis, some growth

factors stimulate ERK and p90 ribosomal S6 kinase (RSK) 1 to inhibit TSC1/2

by phosphorylation and inactivation of TSC2 [23]. However, it should be

mentioned that certain growth factors inhibits Rheb-induced mTORC1

activation via Akt-mediated phosphorylation of PRAS40. (Fig. 1)

Energy and Oxygen supplies

AMP-activated protein kinase (AMPK), a sensitive indicator of cellular

energy status, maintains the balance between intracellular ATP production and

consumption. Under low energy status, AMPK negatively regulates mTORC1

activity through phosphorylating and activating TSC2 or phosphorylating Raptor

to reduce mTORC1 activity [24]. Hypoxia is able to activate TSC1/2 to inhibit

mTORC1 through de novo transcriptional expression of the hypoxia inducible

Redd1 (transcriptional regulation of DNA damage response 1) gene [25].

REDD1 may inhibit mTORC1 through promoting the dissociation of TSC2 from

14-3-3 protein [26].

Amino acids

Amino acids play a pivotal role in stimulating the mTORC1 signaling

activation. In 2008, two independent studies showed that Rag proteins are a

family of four related small guanosine triphosphates (GTPases) that interacts

with mTORC1 in an amino acid-sensitive manner [27]. With specific amino acid

stimulation, RagA/B bound to GTP and RagC/D bound to GDP, which recruits

mTORC1 from the cytosol to the lysosome, and stimulates mTORC1 activation

[28].

Other signals and conditions

In addition to growth factors, oxygen levels and amino acids described

above, some other signals and cellular conditions are able to regulate mTORC1

activity. Inoki K et al. reported that Wnt activates mTORC1 via inhibiting GSK3

without involving beta-catenin-dependent transcription [29]. Lee DF et al. found

that IKKbeta, a major downstream kinase in the TNFalpha signaling pathway,

activates mTORC1 pathway through interacting and phosphorylating TSC1 at

Ser487 and Ser511 [30]. Besides, in response to DNA damage, the p53-

Sestrin1/2 upregulation activates AMPK, which in turn phosphorylates TSC2 to

inhibit mTORC1 activation [31].

Regulation of mTORC2 signaling

In contrast to mTORC1, the activators of mTORC2 signaling are still poorly

defined. Some growth factors may activate mTORC2 kinase through

stimulating the PI3K pathway to phosphorylate Akt at Ser473 [32]. With growth

factors stimulation, PIP3 may recruit mTORC2 and Akt to the plasma

membrane to phosphorylate Akt at Ser473 [33]. It is of note that mTORC1 could

negatively regulate mTORC2 through insulin–PI3K–Akt signaling. Besides

growth factors, AMPK may activate mTORC2 signaling under energetic stress

[34]. (Fig. 1)

Interaction between mTORC1 and mTORC2 signaling

Many studies have revealed a complicated-communication between

mTORC1 and mTORC2 in various cell types. In NK cells, Wang et al. reported

that Raptor-deficiency reduces the abundance of p-Akt (Ser473). In contrast,

Rictor-deficiency increases the abundance of p-S6, suggesting that mTORC1

sustains mTORC2 activity, while mTORC2 negatively regulates mTORC1

activity [35]. In epithelial cells or adipocytes, S6K phosphorylates Sin1 at both

T86 and T398 to inhibit mTORC2 kinase activity by dissociating Sin1 from the

mTORC2 complex [36]. In addition, several lines of evidence showed that

knocking-down Raptor enhances mTORC2 activation by alleviating negative

feedback loops [37]. Recently, our lab demonstrated that ablation of Rictor in

primary cultured kidney fibroblasts largely decreases the S6 phosphorylation,

suggesting mTORC2 may positively regulate mTORC1 signaling in kidney

fibroblasts [38]. Future studies are needed to gradually crack open the mystery

of mTORC1 and mTORC2 cross-regulation.

MTOR in kidney diseases

Acute kidney injury

Acute kidney injury (AKI) is a global health problem with high incidence of

morbidity and mortality. Ischemic, nephrotoxin and sepsis are the common

causes for AKI. A number of studies reported that mTOR signaling maintains

renal tubular homeostasis and inhibits tubular cell death after acute injury [5].

Activation of mTOR signaling in tubular cell protects against AKI [6, 39]. In

addition, our studies showed that activation of mTORC1 and mTORC2

signaling in kidney fibroblasts may stimulate fibroblast to express HGF to

protect against tubular cell death and AKI [38] (Fig. 2).

Administration of rapamycin, an inhibitor of mTORC1, impairs the tubular

cell regeneration and delays the recovery of renal function after AKI [40]. In

addition to directly inhibiting tubular cell proliferation and regeneration,

rapamycin markedly promotes Tregs (CD4+Foxp3+ regulatory T cells) and

MDSCs (Myeloid-derived suppressor cells) recruitment and strengthens their

immunosuppressive activity in the ischemic kidneys [41, 42]. During kidney

transplantation in mice, pre-administration of rapamycin delays tubular

regeneration, exacerbates graft dysfunction and halts post-transplantation

recovery [43]. By contrast, most studies found that administration of rapamycin

in donors markedly attenuates the IRI process, decreases inflammatory

mediators in situ and improves graft function after kidney transplantation [44].

In another report, administration of rapamycin at the early stage of IRI

aggravates kidney dysfunction, while no difference is observed as to kidney

function in mice treated with rapamycin at day 7 after IRI [45] (Table1).

Therefore, the mechanisms of mTOR signaling in regulating renal injury and

recover after transplantation are still not clear.

Renal fibrosis

Chronic kidney disease (CKD) is pathologically manifested as interstitial

excessive extracellular matrix (ECM) deposition and kidney fibrosis. All of the

renal resident cells including fibroblast, tubular epithelial cell, pericyte and

endothelial cell contribute to renal fibrosis. Over the past 20 years, extensive

studies uncovered the pivotal roles for mTOR signaling in the fibrotic kidney

diseases. Rapamycin is able to attenuate interstitial inflammation and kidney

fibrosis in various types of kidney disease including IRI, transplantation,

adriamycin nephropathy, unilateral ureteral obstruction (UUO) and

glomerulopathy [46, 47].

MTOR signaling activation contributes to kidney fibrosis through multiple

pathways. In glomerular mesangial cells, TGFβ1 stimulates miR-21 expression

through PETN/Akt/mTORC1 axis to induce mesangial cell hypertrophy and

matrix expansion [48]. In tubular epithelial cells, rapamycin inhibits mTOR

promoted epithelial-to-mesenchymal transition (EMT) [49]. In kidney fibroblasts

(NRK 49F cell line), TGFβ1 stimulates both mTORC1 and mTORC2 signaling

activation in a time- and dosage-dependent manner, whereas blockade of

mTOR signaling with rapamycin markedly inhibits TGFβ1-induced fibroblast

activation. In mouse kidneys with UUO nephropathy, both mTORC1 and

mTORC2 are activated in interstitial myofibroblasts. Activation of mTORC1

signaling in fibroblasts promotes renal interstitial fibrosis. Ablation of Rictor in

fibroblasts attenuates UUO nephropathy in mice [7, 8, 50]. In macrophages,

mTORC2 signaling activation is indispensable for macrophage M2 polarization

and UUO or IRI-induced kidney fibrosis [51] (Fig 2).

Autophagy is a dynamic process to degrade damaged organelles and

macromolecules. A recent study showed that mTORC1 negatively regulates

autophagy through the association of the late autophagosome and forming the

target of rapamycin (TOR)–autophagy spatial coupling compartment (TASCC),

which promotes profibrotic secretion [52]. Severe kidney injury leads to

increased TASCC formation in tubular cells, more profibrotic factors secretion

and fibrosis progression [53].

Although it is clear that mTOR signaling activation promotes kidney fibrosis,

targeting mTOR for patients with kidney diseases should be cautious.

Rapamycin (mTORC1 inhibitor) and PP242 (dual inhibitor of mTORC1 and

mTORC2) are not cell type-specific inhibitors, which may induce side-effects

during the treatment of patients with kidney diseases.

Podocytopathy

Podocytes are the type of highly differentiated cells with numerous foot

processes that cover the filtration surface area and serve as the selective

permeability of the glomerular filtration barrier. The loss of podocytes leads to

proteinuria, glomerular sclerosis, the progression of kidney dysfunction and

end-stage renal disease (ESRD). A number of studies have shown that mTOR

is crucial to maintain glomerular podocyte morphology and function [9]. MTOR

inhibitors (sirolimus and everolimus) may alter the integrity of the actin

cytoskeleton and decrease cell adhesion to disturb podocyte function [54, 55]

(Table1).

Podocyte-selective deletion of the mTOR gene results in proteinuria and

end stage renal failure [56]. In animal model, ablation of raptor in podocytes

causes proteinuria and progressive glomerulosclerosis. Podocyte-specific

ablation of Rictor results in reduced ability to adapt to stress, suggesting that

mTOR complexes are indispensable for glomerular homeostasis [9].

Podocyte-specific deletion of autophagy-related 5 (Atg5) leads to

glomerulopathy in aging mice [57]. In glomerular injury, aberrant activation of

mTORC1 suppresses podocyte autophagy, damages podocyte function,

deteriorates diabetic kidney disease [10, 58, 59], while rapamycin

administration protects against podocyte injury [60, 61]. Therefore, blockade of

mTOR signaling may activate autophagy to protect against podocytopathy.

In focal segmental glomerulosclerosis (FSGS), mTORC1 target genes are

largely induced in glomeruli, and deletion of one Raptor allele or low-dose

rapamycin treatment retards the progression of glomerulosclerosis [62].

However, in patients with FSGS, mTOR inhibitors show conflicting results,

ranging from remission to deterioration of kidney dysfunction [63-65]. In IgA

nephropathy and lupus nephritis, mesangial cell mTORC1 activation induces

the production of collagen IV, collagen I, and α-smooth muscle actin in glomeruli

[66]. Rapamycin may reduce the level of anti-double-stranded-DNA antibodies,

suppresse the infiltrate of inflammatory cells in lupus model. In IgA nephropathy,

rapamycin attenuates IgA deposition in the glomeruli to protect renal function

[15, 67]. MTOR inhibitors have also been shown to decrease proteinuria, the

proliferation of mesangial and endocapillary, improve immunoregulation and

renal function in patients with IgA nephropathy and Lupus Nephritis [68-70]

(Table1).

In summary, mTOR plays an important pathogenic role in glomerular

diseases. Several studies suggested that mTORC1 inhibition may reduce

glomerular hypertrophy, albuminuria, and prevent the progression of glomerular

diseases in animal models. However, in patients, rapamycin treatment

frequently causes podocyte apoptosis, proteinuria, and focal segmental

glomerulosclerosis [71, 72]. The underlying mechanisms remain obscure.

Polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) due to PKD1 or

PKD2 gene mutation is one of the most common human monogenic diseases.

MTOR has been demonstrated to play an important role in cyst formation and

enlargement in PKD. Several studies showed that the cytoplasmic tail of PC1

interacts with tuberin to form a complex and functions as the endogenous

inhibitor for Rheb, a constitutive mTORC1 activator. The multiprotein complex

inappropriately activates mTORC1 when PC1 is mutated in tubular epithelial

cells to promote cyst formation and PKD in patients and animal models [11].

PC1 regulates mTORC1 activation relying on ERK-mediated TSC2

phosphorylation. In the absence of PC1, ERK may phosphorylate tuberin at

Ser664 to activate mTORC1 signaling [12]. Metformin inhibits mTORC1 and

cyst growth in mouse model with ADPKD through stimulating AMP-activated

protein kinase (AMPK) [73]. A recent study revealed that in Tsc1-mutant mice,

Afadin, a component of cell adhesion systems, is directly phosphorylated by

S6K1, which affects oriented cell division and promotes kidney cyst formation

[74].

In the early 21st century, two groups demonstrated that rapamycin and

sirolimus can obviously reduce cell proliferation in cystic and noncystic tubule,

retard the progression of cystogenesis, and protect kidney function in

Han:SPRD rats with ADPKD [75, 76]. A number of subsequent studies

confirmed these findings [77, 78]. Besides, researchers also reported some

other pathways including PI3K, Erk, cAMP, and mTORC2 are activated in

ADPKD [79-81]. Shillingford JM et al. found that rapamycin treatment largely

reduces native polycystic kidney size in ADPKD transplant-recipient patients

[11]. Recently, the clinical trials for mTOR inhibitors in patients with ADPKD

have been extensively employed (Table1). In some clinical trials, mTOR

inhibitors cannot significantly decrease the total kidney volume (TKV), halt

polycystic kidney growth, or slow the progression of renal impairment compared

with placebo groups [82-84], which may be attributed to the short follow-up

period, low blood concentration in cystic tissue, and advanced disease stage in

patients [82, 84]. Whereas high-dose of mTOR inhibitor treatment decreases

the progress of cystogenesis, halts cyst growth and increases parenchymal

volume in patients with ADPKD [85]. Although mTOR inhibitors have been

shown effective in treating ADPKD in animal models, for ADPKD patients, the

optimal time points and the dosage for mTOR inhibitors are still needed to be

deciphered.

Renal cell carcinoma

Renal cell carcinoma (RCC) originated in the renal cortex accounts for 2-3%

of all adult malignancies. The mutations of VHL gene lead to the upregulation

of hypoxia-inducible factor (HIF), VEGF, PDGFβ and TGFβ to stimulate tumor

angiogenesis and proliferation [86]. The VEGF-R and PDGF-R signaling

activate the PI3K–AKT-mTORC1 pathway. In turn, mTOR pathway may

activate HIF1α to constitute a positive feedback loop between VHL and mTOR

in RCC [13]. Hence, mTOR signaling may be a potential therapeutic target in

RCC [87].

Several mTOR signaling inhibitors including mTOR kinase domain inhibitors

[16], mTOR/PI3K dual inhibitors [88], PI3K-selective inhibitors, and a pro-

apoptotic protein named programmed cell death 6 (PDCD6) have been used in

the treatment of RCC [89] (Table1). A novel dual mTORC1/2 inhibitor AZD-

2014 disrupts mTORC1/2 assembly and activation to promote RCC cell death

[90]. Unfortunately, in a randomized Phase II study, the Progression-free

survival (PFS) and overall survival (OS), of AZD2014 are inferior to everolimus

in the refractory metastatic RCC [91] (Table1).

Conclusion

Over the past decades, numerous studies have demonstrated that mTOR

signaling plays an important role in renal physiology and disease. Transient

mTOR signaling activation in tubular cells or fibroblasts is beneficial for renal

repair after AKI, but continuing mTOR signaling activation stimulates

extracellular matrix deposition and renal fibrosis in mice. Similarly, mTOR

complexes are indispensable for maintaining glomerular homeostasis and

aberrant activation of mTORC1 leads to podocyte dysfunction and albuminuria.

In ADPKD and renal cell carcinoma, mTOR signaling activation plays a

pathogenic role through promoting renal cyst formation and RCC cell survival.

Although the roles of mTOR in renal physiology and disease have been

considerably explored, much still remain to be uncovered. The usage of mTOR

inhibitors in kidney transplantation, ADPKD, and RCC need more assessment.

Further exploration is needed to define optimal treatment time points, the

dosage, combined therapies, and cell type specific medications in treating

patients with various type of kidney disease. Notably, the intertwine

mechanisms between mTORC1 and mTORC2 signaling in kidneys need to be

deciphered.

Disclosures

All authors have nothing to disclose.

Funding

National Science Foundation of China: Yuan Gui, Chunsun Dai,

81570611/H0503; 81770675/H0503

Author Contributions

Y Gui: Formal analysis; Writing - original draft; Writing - review and editing

C Dai: Investigation; Supervision; Writing - review and editing

Table 1 | The effects of mTOR inhibitors in renal diseases. Animal studies Clinical studies Acute kidney injury delayed the recovery of renal function[40, 92] prolongation of DGF[43, 93]

Renal fibrosis abolished TGFβ1-induced fibroblast activation and kidney interstitial fibrosis[8]

None

Podocyte homeostasis disturbed podocyte function and developed proteinuria[54, 55, 94]

None

Diabetic nephropathy reduced albuminuria and glomerular enlargement, and attenuates renal hypertrophy[9, 95]

Sirolimus therapy induced proteinuria following CIT[96]

Focal segmental glomerulosclerosis ameliorated the progression of glomerulosclerosis[62] Conflicting results, ranging from remission to deterioration of kidney function[63-65]

IgA nephropathy reduced IgA deposition[67] Improved GFR, decreased proteinuria and mesangial and endocapillary proliferation[70]

lupus mesangial proliferative nephritis reduced the level of anti-dsDNA antibodies, suppressed the infiltrate of inflammatory cells[15]

improved immune-regulation, renal function and proteinuria[68, 69]

Polycystic kidney disease decreased cystogenesis and TKV, improved kidney function[76, 78]

controversial[11, 83]

Renal cell carcinoma AZD-2014 inhibited RCC cell survival and growth, and enhanced autophagy[90]

without great success in treating renal cancer[97]

DGF, delayed graft function; CIT, clinical islet transplantation; GFR, glomerular filtration rate; anti-dsDNA antibodies, anti-double-stranded-DNA antibodies; TKV, total kidney volume

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Figure 1

Figure 1. Diagram of intracellular mTOR signaling cascade. mTOR is a

component of two major intracellular signaling complexes: mTORC1 and

mTORC2. MTORC1 is formed by mTOR, Raptor, mLST8, PRAS40, and Deptor.

MTORC2 is formed by mTOR, mLST8, Deptor, Rictor, mSIN1, and PROTOR1/2.

mTORC1 is activated by growth factors and amino acids through PI3K–Akt

pathway. Activated Akt inhibits the TSC1/2. TSC1/2 negatively regulates

mTORC1 signaling by acting as GTPase-activating protein for Rheb. Under low

energy status, AMPK negatively regulates mTORC1 activity. Hypoxia is able to

activate TSC1/2 to inhibit mTORC1 through Redd1 gene. Besides, Wnt

activates mTORC1 via inhibiting GSK3β. Abbreviations: mTOR: mammalian

target of rapamycin; Raptor: regulatory-associated protein of mTOR; PRAS40:

proline-rich AKT substrate 40 kDa; Deptor: DEP-domain-containing mTOR-

interacting protein; mLST8: mammalian lethal with Sec13 protein 8; Rictor:

rapamycin-insensitive companion of mTOR; mSIN1: mammalian stress-

activated protein kinase interacting protein 1; PROTOR1/2: protein associated

with rictor 1 or 2; TSC1: tuberous sclerosis complex 1; TSC2: tuberous sclerosis

complex 2; PI3K: phosphoinositide 3 kinase; PDK1: phosphoinositide-

dependent protein kinase 1; AMPK: AMP-activated protein kinase; Redd1:

transcriptional regulation of DNA damage response 1.

Figure 2

Figure 2. Diagram of mTOR signaling activation in acute kidney injury and

kidney fibrosis. In response to acute injury, tubular epithelial cells undergo

injury and death. Activated mTOR signaling in kidney fibroblasts facilitates

tubular cell survival and proliferation via PPARγ and HGF induction. In chronic

kidney disease, mTOR signaling activation promotes fibroblast and

macrophage activation and proliferation to produce ECM and renal fibrosis.