Proteinuric Kidney Disease/Nephrotic Syndrome: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Ryosuke Saiki
,
Kan Katayama
,
Kaoru Dohi

Proteinuria is known to be associated with all-cause and cardiovascular mortality, and nephrotic syndrome is defined by the level of proteinuria and hypoalbuminemia. With advances in medicine, new causative genes for genetic kidney diseases are being discovered increasingly frequently.

  • genetic kidney disease
  • knockout
  • nephrotic syndrome

1. Introduction

Nephrotic syndrome (NS) is defined by proteinuria and hypoalbuminemia associated with edema and hyperlipidemia. General edema and pleural effusion are observed in severe cases, and NS is a cause of end-stage kidney disease (ESKD). Even slight proteinuria affects all-cause and cardiovascular mortality [1]. NS consists of steroid-sensitive NS (SSNS) and steroid-resistant NS (SRNS). A previous report suggested that approximately 30% of SRNS cases were caused by a single gene abnormality [2]. Hereditary types of NS that appear in both familial and nonfamilial patients and manifest throughout a wide age range and spectrum of histological abnormalities have been linked to numerous genes. To name a few of the more famous ones, podocyte-specific genes include NPHS1, NPHS2, WT-1, PLCE1, LMX1B, SMARCAL1, COQ2, CD2AP, ACTN4, TRPC6, and INF2. As glomerular basement membrane (GBM) components, COL4A3, COL4A4, COL4A5, and LAMB2 have been identified as major causes [3]. The GBM is an essential component of the glomerular filtration barrier and is also related to proteinuria [4]. For example, a loss of GBM heparan sulfate chains, major components of the GBM, is associated with proteinuria in several glomerular diseases, including lupus nephritis and diabetic nephropathy [4][5][6]. Moreover, mature podocytes produce high levels of VEGF-A, and adult glomerular endothelial cells (GECs) express high levels of VEGF receptors, which indicates that podocytes and GECs are related to each other [7]. For example, RRM2B deletion shows the marked endothelial hypertrophy in addition to progressive podocyte hypertrophy [8]. GEC dysfunction is characterized by a compromised endothelial glycocalyx, an inflammatory phenotype, mitochondrial damage and oxidative stress, aberrant cell signaling, and endothelial-to-mesenchymal transition in the early stages of focal segmental glomerular sclerosis (FSGS) and diabetic kidney disease (DKD) [9]. The endothelium may play a role in some glomerular diseases because it involves alterations of the systemic and glomerular endothelium and glycocalyx, and their sera directly activate GECs [10]. Glomerular endothelial cell failure is sufficient to promote podocyte damage, proteinuria, and mesangial cell activation [9]. With advances in medicine, new causative genes for genetic kidney diseases are being discovered increasingly frequently.

2. Proteinuria/NS

Many genes that are related to proteinuria and NS have been discovered so far, and an overview of the genes is shown in Figure 1.
Biomedicines 11 01803 g001
Figure 1. (a) AIM2 promotes podocyte differentiation and suppresses proliferation by increasing WT1 and cell cycle genes such as CDKN1A. (b) TWIST1 inhibits CCL2 induction which promotes monocyte/macrophage infiltration into the injured glomeruli. (c) GSK α/β knockout causes mitotic catastrophe. (d) If WTIP is retained in the nucleus, WTIP associates with WT1 and inhibits WT1-dependent transcriptional activation of the amphiregulin promoter. (e) WT1 is both a transcriptional repressor and activator and regulates genes important in nephron formation including podocalyxin, amphiregulin, and perhaps nephrin. (f) REST maintains cytoskeleton homeostasis protects against apoptosis and maintains kidney function during aging. (g) IL1RAP induces suppressive immune cells called myeloid-derived suppressor cells (MDSCs). (h) SLK is a regulator of cytoskeletal structure. (i) PALD1 regulates actin filaments, synaptopodin, and α-actinin-4. (j) GADD45GIP1 plays an essential role in mitochondrial synthesis and membrane integration of OXPHOS polypeptides. (k) SHROOM3 is related to Fyn activation and nephrin phosphorylation. (l) NES regulates nephrin. (m) EXOC5 affects the expression and localization of nephrin. (n) PP2A is involved in the expression of synaptopodin, podocin, nephrin. (o) LAMA5 encodes Laminin-α5. (p) USP40 is colocalized with NES in developing and mature podocytes. Its deficiency upregulates NES.
Absent in melanoma-2 (AIM2) is an innate immune sensor for cytosolic dsDNA and localizes to podocytes in the kidney [11]. Aim2−/− mice showed crescent formation after intravenous administration of nephrotoxic serum compared to wild-type (WT) mice, which was associated with podocyte dedifferentiation and parietal epithelial cell activation [11].
BMAL1 is the protein at the core of the circadian clock and regulates the transcription of various clock-controlled genes [12]. Loss of Bmal1 in the kidney can result in various alterations in the renal physiological function, such as lowering blood pressure, disrupting fluid–electrolyte balance, and changing the glomerular filtration rate [13]. The urinary albumin/creatinine ratio, serum creatinine, and blood urea nitrogen values were elevated in proximal tubular cell-specific Bmal1 knockout mice fed an adenine diet compared to WT mice [14].
CRIF1 plays an essential role in mitochondrial synthesis and membrane integration of oxidative phosphorylation polypeptides, interacting with proteins surrounding the polypeptide exit tunnel of the large subunit of mitochondrial ribosomes [15]. Podocyte-specific Crif1 knockout mice exhibited progressive albuminuria and kidney dysfunction [16]. Electron microscopic analyses demonstrated mitochondrial structural abnormalities, such as abnormal arrangement and loss of cristae as well as podocyte foot process effacement [16].
The exocyst complex comprises eight proteins that have been shown to play vital roles in exocytosis and vesicle trafficking [17]. Two patients with deletions in EXOC4 were identified among 256 patients with NS [15]. Podocyte-specific Exoc5 knockout mice showed massive proteinuria, foot process effacement, and loss of slit diaphragm as well as mislocalization of nephrin and Neph1 [18].
GALNT11 encodes a member of the large glycosyltransferase family responsible for initiating mucin-type O-glycosylation of secreted and membrane-bound proteins [19]. Galnt11 was specifically expressed in the mouse proximal tubules similar to expression patterns seen in human kidneys, and Galnt11 knockout mice displayed increased albumin-to-creatinine ratios relative to controls, suggesting that Galnt11 had an effect on reabsorbing albumin in the proximal tubules [20].
Glycogen synthase kinase-3 (GSK3) has two isoforms, GSK3α and GSK3β, and plays a role in phosphorylation, protein complex formation, and subcellular distribution [21]. Podocyte-specific GSK3 α/β knockout mice (podCreGSK3αfl/flβfl/fl) had enlarged pale kidneys, kidney failure, and high levels of albuminuria [22]. Podocin RtTA-tet-o-Cre GSK3αfl/flβfl/fl mice given doxycycline from four weeks old developed a spectrum of kidney disease, ranging from mild albuminuria or mesangial hypercellularity to glomerulosclerosis and interstitial fibrosis [22]. These data showed essential roles of GSK3 α/β in the developmental and maturity periods [22].
Although many causative genes with SRNS have recently been discovered, not much is known about the genes associated with SSNS, which accounts for approximately 80% of childhood-onset NS [23]. Analyzing a case of familial SSNS indicated the potential causative gene to be IL1RAP, which encoded an essential common subunit of the functional IL-1, IL-33, and IL-36 receptors [24]. Peripheral blood mononuclear cells in SSNS patients showed a decreased response to IL-1β. Furthermore, Il1rap knockout mice exhibited exacerbated lipopolysaccharide (LPS)-induced nephrotic albuminuria [24].
Mutations in six genes—MAGI2, TNS2, DLC1, CDK20, ITSN1, and ITSN2—were found in seventeen families with NS [25]. Although there were no marked differences between Itsn2L−/L− and WT mice in the histologic findings of the kidneys or level of urinary protein, LPS injection increased urine albumin levels in Itsn2L−/L− mice compared to WT mice [25]. There was also a delayed recovery from podocyte injury in Itsn2L−/L− mice compared to WT mice [25].
The LAMA5 gene encodes Laminin-α5, and Lama5−/− mice exhibited embryonic lethality and severe defects in glomerular development [26]. Three hundred families with pediatric NS underwent whole-exome sequencing, which revealed homozygous variants in LAMA5 in three families [27]. These genetic variants might contribute to the development of NS in pediatric patients.
PALLD plays a critical role in the stability and dynamics of the actin cytoskeleton [28]. Podocyte-specific Palld knockout showed disrupted morphology of the glomeruli with mild podocyte foot process effacement and increased susceptibility to nephrotoxic serum [28].
Podocyte-specific PP2A knockout mice exhibited weight loss, growth retardation, and proteinuria associated with progressive glomerulosclerosis, interstitial fibrosis, and foot process effacement [29]. Upregulation of phosphorylated YB-1 was observed in podocyte-specific PP2A knockout mice and might be related to the functional integrity of glomerular filtration [29].
Repressor element 1-silencing transcription factor (REST) is a repressor of neuronal genes during embryonic development [30]. Although REST is downregulated after terminal neuronal differentiation, it is induced in the aging human brain and regulates a network of genes that mediate cell death and stress resistance [30]. Podocyte-specific Rest knockout mice developed albuminuria, glomerulosclerosis, and interstitial fibrosis [31]. Furthermore, REST was found to be induced by oxidative stress and protected against apoptosis in podocytes [31].
Shroom3 is an F-actin binding protein that is important for epithelial morphogenesis [32]. Although tubular-specific Shroom3 knockdown in mice inhibited kidney fibrosis in a ureteric obstruction model [32], glomerular and podocyte-specific Shroom3 knockdown induced reversible albuminuria with podocyte foot process effacement without podocyte loss [32][33].
Ste20-like kinase (SLK) is a serine/threonine kinase expressed ubiquitously and appears to be a regulator of cytoskeletal structure [34]. Podocyte-specific Slk knockout mice injected with adriamycin showed a decreased number of podocytes and greater albuminuria than control mice [34]. Ezrin levels and ezrin phosphorylation were reduced in podocyte-specific Slk knockout mice injected with adriamycin, which was associated with the decreased expression of F-actin and alteration of the shape of podocytes [34].
Twist1 is a transcriptional repressor and inhibits cytokine production by diminishing NF-κB or Runx3 expression in Th1 cells [35]. Twist1 in podocytes limited CCL2 production and macrophage infiltration in injured glomeruli [36]. Although podocyte-specific Twist1 knockout mice did not exhibit proteinuria, they had more proteinuria than WT mice after inducing nephrotoxic serum or adriamycin [36].
The degradation systems for cellular proteins consist of the ubiquitin proteasome system and the autophagosome–lysosomal pathway, central to which is the conjugation of ubiquitin to substrate proteins [37]. Deubiquitinating enzymes (DUBs) make ubiquitination reversible, slowing the ubiquitination process by removing ubiquitin chains or inhibiting the catalytic function of ubiquitin-related enzymes [38]. Ubiquitin-specific protease (USP) is the largest family of DUBs, and USP40 is specifically localized in the podocytes of the mature glomerulus [38]. Cultured podocytes with USP40 knockdown decreased HINT1 and p53 [39]. Although Usp40 knockout mice did not exhibit any alterations in the glomerular phenotype, USP40 and its interacting partners formed a regulatory network that protected the cellular processes leading to glomerular sclerosis [39].
WTIP is part of a multiprotein complex in the podocyte foot process and shuttles between the nucleus and cytosol [40]. Wtip−/− mice exhibited embryonic lethality, and Wtip heterozygous mice developed significant proteinuria in response to LPS or adriamycin injection compared to WT mice [41]. Further studies involving podocyte-specific Wtip knockout mice are desirable.

3. Focal Segmental Glomerular Sclerosis (FSGS)

FSGS is the most common glomerular histologic lesion associated with high-grade proteinuria and ESKD, which can be caused by a variety of underlying mechanisms [42]. In individuals who either do not receive treatment or are refractory to it, primary FSGS is often a progressive condition, with a 5% rate of spontaneous remission and a 50% rate of ESKD during a period of 5–8 years following a biopsy [42]. Up to two-thirds of patients with FSGS who present in the first year of life have genetic abnormalities that account for the later clinical presentation in this age range [42]. However, in older children and adults with FSGS and a related genetic mutation, the direct causal relationship with the disease process, such as proteinuria and kidney failure, is not as clear. In this situation, it has been proposed that a second hit might be necessary [42]. There are many theories as to where these triggers come from, including additional genetic and/or outside environmental elements [42]. Further investigations into causal genes might provide more information on treatment efficacy and the kidney prognosis.
Polymorphisms in APOL1 are a risk factor for chronic kidney disease (CKD), including human immunodeficiency virus (HIV)-associated nephropathy and FSGS [43]. The common allele (known as G0) reduced glomerulosclerosis in a murine model of HIV-associated nephropathy compared to the CKD-associated risk alleles, known as variants G1 and G2 [43]. The APOL1 G1 risk allele made mice more susceptible to kidney disease in a lipotoxicity-driven FSGS model [44]. Intravenous injection of interferon γ led to heavy proteinuria and glomerulosclerosis in G1/G1 and G2/G2 but not G0/G0 bacterial artificial chromosome (BAC) transgenic mice [45]. Transmission electron microscopic analyses of human urinary podocytes showed a reduced mitochondrial matrix density and increased mitochondrial area in G1/G2 podocytes compared with G0/G0 podocytes [44]. Antisense oligonucleotides against APOL1 mRNA reduced protection against IFN-γ–induced proteinuria in APOL1 G1 mice [46]. In humans with two APOL1 variants (G1/G1, G2/G2 or G1/G2), inaxaplin selectively inhibited the APOL1 channel function and reduced proteinuria in a phase 2a study [47]. Further studies will be expected in the future.
Rho GTPases, such as RhoA, Rac1, and Cdc42, are regulators of the actin cytoskeleton and play important roles in podocyte morphology and ensuring an efficient barrier function [48]. Arhgef7 is an important activator of Cdc42, and podocyte-specific Arhgef7 knockout mice exhibited progressive proteinuria and FSGS with reduced Cdc42 activity [49].
COQ6 is needed for the biosynthesis of coenzyme Q10, and its mutations in human patients produce NS with sensorineural deafness [50]. Recently, a new mutation of COQ6 c.41G>A was detected in a patient with FSGS [51]. Podocyte-specific Coq6 knockout mice developed proteinuria and FSGS [52]. However, podocyte-specific Coq6 knockout mice treated with 2,4-dihydroxybenzoic acid, which functioned to bypass certain deficiencies of the CoQ10 biosynthesis pathway, were protected from kidney disease progression, showing an improved survival compared to untreated mice [52].
Crb2 is a type I transmembrane protein that is expressed in the apical membrane of podocytes [53]. Podocyte-specific Crb2 knockout mice had severe albuminuria, FSGS, and tubulointerstitial fibrosis associated with a decreased expression of Nphs2, Podxl, and Nphs1 [53]. CRB2 protein variants with SRNS accumulated in the endoplasmic reticulum (ER), exhibited altered glycosylation patterns, and induced an ER stress response [54].
MYO9A has a Rho-guanosine triphosphatase activating protein (Rho-GAP) tail domain that deactivates RhoA [55]. Myo9aR701X/+ mice showed proteinuria and FSGS with increased RhoA activity, which recapitulated autosomal dominant inheritance of the heterozygous MYO9A p. R701X variant identified in the proband [55].
PARVA controls RhoA/ROCK-mediated contractility [56]. Podocyte-specific Parva knockout mice exhibited proteinuria and FSGS, which resulted in kidney dysfunction [57][58]. PARVA associated with TJP1 (also known as ZO-1) and prevented lysosome-dependent degradation of TJP1, which contributed to maintaining the podocyte structure and function [57]. Podocyte-specific Tjp1 knockout mice showed proteinuria and GS with impaired slit diaphragm formation; in addition, podocyte-specific Tjp1 and Tjp2 double-knockout mice showed the accelerated appearance of the defects observed in podocyte-specific Tjp1 knockout mice [59].
Urokinase-type plasminogen activator receptor (uPAR) is a glycosyl-phosphatidylinositol (GPI)-anchored protein, and soluble uPAR (suPAR) is generated by removal of the GPI anchor from uPAR [48]. suPAR can be detected in blood and urine and serves as both an inflammatory biomarker and a signaling molecule [60]. suPAR isoform-2 transgenic mice developed albuminuria and FSGS with podocyte foot process effacement [61].
Phosphatidylserine is asymmetrically and dynamically distributed across the lipid bilayer in eukaryotic cell membranes, which is maintained by flippases, one of the most important P4-ATPases [62]. The TMEM30 (also known as CDC50) family proteins interact with multiple P4-ATPases [63], and the TMEM30A expression was shown to be decreased in patients with minimal change disease and membranous nephropathy (MN) [64]. Podocyte-specific Tmem30a knockout mice showed albuminuria and FSGS, which was associated with ER stress [64].
Zinc finger and homeobox (ZHX) family transcription factors, such as ZHX1, ZHX2 and ZHX3, regulate the majority of structurally and functionally important podocyte genes, and ZHX2 is one of the most potent transcriptional repressors of WT1 [65]. While podocyte-specific Zhx2 knockout mice did not show albuminuria compared to control mice, podocyte-specific Zhx2 transgenic rats showed more proteinuria than WT rats after adriamycin injection [65].

4. MN (Membranous Nephropathy)

MN is a kidney glomerular condition that is diagnosed pathologically and is characterized by thickening of the glomerular capillary walls caused by the development of immune complexes on the outer portion of the basement membrane [66]. MN accounts for 30% of adult cases of nephrotic syndrome. In 80% of MN patients, there is no underlying etiology of MN, while 20% of cases are associated with drugs, such as nonsteroidal anti-inflammatory drugs, or other disorders, such as systemic lupus erythematosus, hepatitis B or C, and malignancies [66]. Although MN is not a typical Mendelian hereditary disease, emerging evidence suggests a significant genetic component [66].
A 40-year-old woman with Charcot–Marie–Tooth disease developed nephrotic range proteinuria due to MN, and a genetic analysis identified a heterozygous nonsense variation in exon 2 of the MPZ gene [67]. MPZ is an integral membrane glycoprotein and is essential for membrane adhesion [68]. Mutations in MPZ were associated with Charcot–Marie–Tooth disease, and Mpz−/− mice exhibited higher rates of albuminuria and GBM thickening than WT mice [68].
NPNT is an extracellular protein localized in the GBM, and injection of miR-378a-3p, which targets NPNT, led to albuminuria and podocyte foot process effacement in mice [69]. Podocyte-specific Npnt knockout mice showed proteinuria and widening of the lamina rara interna of the GBM [70].

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11071803

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