calculating proximal tubule cell number10.1208... · web viewusing these two values as the minimum...

Supplementary Material for “Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data” by Scotcher et al.

Contents1. CALCULATING PROXIMAL TUBULE CELL NUMBER..................................................................................1

2. TABLE S-I.............................................................................................................................................. 3

3. TABLE S-II............................................................................................................................................. 7

4. TABLE S-III.......................................................................................................................................... 10

5. TABLE S-IV.......................................................................................................................................... 13

6. REFERENCES FOR TABLES I AND IV AND FIGURE 3 IN MAIN TEXT.........................................................15

7. REFERENCES....................................................................................................................................... 16

1. Calculating proximal tubule cell number Strategy 1. Multiplying “number of proximal tubule cells per mm proximal tubule” by “total length of proximal tubule in kidney”

PTCd = 6.1 cells/ cross section proximal tubule (1)

PTCl = 3.6 cells/ 100 µm proximal tubule length (1)

LPT = 18 mm (2)

NPT = 900,000 proximal tubules per kidney (3-5)

PTCkidney=PTCd× PTC l× LPT×N PT

PTCkidney = 3.95 billion proximal tubule cells per kidney

Where PTCd, PTCl and PTCkidney are the number of proximal tubule cells per cross section of proximal tubule, per 100 µm proximal tubule length and per human kidney, and LPT and NPT

are the average length and number of proximal tubules per human kidney, respectively.

The reported values of total proximal tubule cells per mm of proximal tubule (i.e. PTCd

×PTCl) in rabbit were 278, 281 and 204 for segments S1, S2 and S3, 300 and 825 cells/ mm tubule (6-8), although these were not measured using stereological methodology. Analogous values for the cellularity of other regions of the nephron have also been reported for rabbit (8). The corresponding value calculated as above for human was at the lower end of this range, 219.6 proximal tubule cells per mm proximal tubule.

Assuming a kidney weight of 131 g (4), it follows that there are approximately 30.2 million proximal tubule cells per gram kidney. Further assuming that the cortex contributes 72% of kidney volume (and also mass) (9), 41.9 million proximal tubule cells per gram cortical kidney tissue is calculated.

1

Strategy 2. Dividing total volume of proximal tubule epithelium wall by volume of a single proximal tubule cell.

If the volume of the proximal tubule epithelium is assumed to be 0.00148 mm3/ mm tubular length (10), and the proximal tubule length and number of proximal tubules per kidney assumed to be 18 mm and 900,000 tubules/ kidney as above, the total volume of proximal tubule epithelium can be calculated as 23976 mm3/ kidney. Alternatively, if the total volume of cortex is assumed to be 106 mL/ kidney (average of male and female for all ages) (9), and that 34.9% of cortex is proximal tubule epithelium by volume (10), then the total volume of proximal tubule epithelium can be calculated as 36990 mm3/ kidney.

Using these two values as the minimum (23976 mm3/ kidney) and maximum (36990 mm3/ kidney) volume of proximal tubule epithelium, and 1350 and 3521 µm3 as the minimum and maximum volumes of a single proximal tubule cell (11-13), the inferred number of proximal tubule cells ranges from 6.81 to 27.40 billion cells/ kidney. This equates to 52.0 to 209.2 million proximal tubule cells/ gram kidney (assuming kidney weight of 131 g (4)).

2

2. Table S-I Table S-I. Expression of SLC Family Drug Transporters in the Human and Rodent Kidney

Human Rodent

Transporter(Gene)

Kidney Abundance(Method; Region)

KidneyLocalisation(Method)

Cell Localisation(Method)

Transporter(Gene)




hOCT1

(SLC22A1)

+ (RT-PCR; NS) (14)+ (MA; NS) (15)- (RT-PCR; NS) (16)+ (RT-PCR; NS) (17)+ (NS; NS) (18)- (RT-PCR; C) (19)+ (RT-PCR) (20)

PT, DT (IHC) (18) AP (IHC) (18) rOCT1

(Slc22a1)

5.20 fmol/µg (MS; K) (21) c

+++ (BDA; NS) (22)+ (BDA; NS) (23)+++ (MA; NS) (15)+ (BDA; NS) (24)

S2, S3>S1 (ISH) (25)S1, S2>S3 (IHC) (25)C>OS (IHC) (26)

BL (IHC, WB) (25)

mOCT1

(Slc22a1)

+++ (BDA; NS) (27)

hOCT2

(SLC22A2)

++ (RT-PCR; NS) (14)+++ (MA; NS) (15)++ (RT-PCR; NS) (16)++ (RT-PCR; NS) (17)++ (RT-PCR; C) (19)+ (RT-PCR; C) (28)

PT (IHC) (18)PT (IHC) (19)DT (ISH, IHC) (29) a

BL (IHC) (18)BL (IHC) (19)AP (IHC) (29)

rOct2

(Slc22a2)

+++ (BDA; NS) (22)+ (BDA; NS) (23)+++ (MA; NS) (15)+++ (BDA; NS) (24)

OS>C (ISH) (25)S2, S3>S1 (IHC) (25)OS>C (IHC) (26)

BL (IHC, WB) (25) BL (WB) (26)

mOct2

(Slc22a2)

+++ (BDA; NS; Male) (27)++ (BDA; NS; Female) (27)

hOCT3

(SLC22A3)

+ (RT-PCR; NS) (14)+ (MA; NS) (15)+ (RT-PCR; NS) (16)- (RT-PCR; NS) (17)+(RT-PCR; C) (19)

C>M; PT, DT (ISH) (30)

rOct3

(Slc22a3)

++ (BDA; NS) (22)+ (BDA; NS) (23)+ (MA; NS) (15)- (BDA; NS) (24)

mOct3

(Slc22a3)

- (MS; C; M) (31) b

- (BDA; NS) (27)

hOCTN1

(SLC22A4)

+ (RT-PCR; NS) (14)++ (MA; NS) (15)+ (RT-PCR; NS) (16)- (RT-PCR; NS) (17)- (RT-PCR; C) (19)

rOctn1

(Slc22a4)

++ (BDA; NS) (22)+ (BDA; NS) (23)++ (MA; NS) (15)- (BDA; NS) (24)

OS> C, M; G, PT, DT (ISH) (32)

mOctn1 + (BDA; NS) (27) C; PT (IHC) (33) AP (33)

3

Human Rodent

Transporter(Gene)




Transporter(Gene)




(Slc22a4)

hOCTN2

(SLC22A5)

++ (RT-PCR; NS) (14)+++ (MA; NS) (15)+ (RT-PCR; NS) (16)++ (RT-PCR; NS) (17)+ (RT-PCR; C) (19)

PT (IHC) (34) AP (34) rOctn2

(Slc22a5)

+++ (BDA; NS) (22)+ (BDA; NS) (23)+++ (MA; NS) (15)+++ (BDA; NS) (24)

C; G, PT, DT (ISH) (35)PT (IHC) (36)

AP (IHC) (36)

mOctn2

(Slc22a5)

++ (BDA; NS) (27) C; PT (IHC) (33) AP (33)

rOctn3

(Slc22a9)

S2, S3 (IHC) (37) AP (IHC) (37)

mOctn3

(Slc22a9)

+ (RT-PCR, WB; NS) (38)- (BDA; NS) (27)

hOAT1

(SLC22A6)

+++ (RT-PCR; NS) (14)+++ (MA; NS) (15)+++ (RT-PCR; NS) (16)+++ (RT-PCR; NS) (17)++ (RT-PCR; C) (19)++ (RT-PCR; C) (28)

PT (IHC) (39)PT (IHC) (19)

BL (IHC) (39)BL (IHC) (19)BL (IHC) (28)

rOat1

(Slc22a6)

10.5 fmol/ µg (MS; K) (21) c

+++ (BDA; NS) (22)+++ (BDA; NS) (23)++ (BDA; NS) (24)

C (WB); PT (IHC) (40)PT, Male>Female (IHC) (41)

BL (IHC) (40)BL (IHC) (41)

mOat1

(Slc22a6)

12.7 fmol/ ug (MS; C) (31) b

3.00 fmol/ µg (MS; M) (31) b

C, PT (IHC) (42)S1, S2 (IHC) (43)

BL (IHC) (42)BL (IHC) (43)

hOAT2

(SLC22A7)

+ (RT-PCR NS) (14)+++ (MA; NS) (15)+ (RT-PCR; NS) (16)+ (RT-PCR; NS) (17)+ (RT-PCR; C) (19)++ (RT-PCR; C) (28)

PT (IHC) (44) BL (IHC) (44)BL (IHC) (28)

rOat2

(Slc22a7)

+ (BDA; NS) (22)++ (BDA; NS) (23)- (BDA; NS) (24)

TAL (IHC) (45)S3, F>M (IHC, WB) (46)

AP (IHC) (45)AP (IHC) (46)

mOat2

(Slc22a7)

S3, F>M (IHC, WB) (46)

AP (IHC) (46)

hOAT3

(SLC22A8)

+++ (RT-PCR; NS) (14)+++ (MA; NS) (15)++ (RT-PCR; NS) (16)+++ (RT-PCR; NS) (17)+++ (RT-PCR; C) (19)

PT (IHC) (47)PT (IHC) (19)

BL (IHC) (47)BL (IHC) (19)BL (IHC) (28)

rOat3

(Slc22a8)

6.71 fmol/ µg (MS; K) (21) c

+++ (BDA; NS) (22)+++ (BDA; NS) (23)+++ (BDA; NS) (24)

PT, TAL, CD (IHC) (45)S1, S2, S3 (IHC) (48)

BL (IHC) (45)BL (IHC) (48)

mOat3 4.66 fmol/ µg (MS; C) (31) b S1, S2, S3, TAL, DT, BL (IHC) (43)

4

Human Rodent

Transporter(Gene)




Transporter(Gene)




+++ (RT-PCR; C) (28) (Slc22a8) 0.94 fmol/ µg (MS; M) (31) b CD (IHC) (43)

hOAT4

(SLC22A11)

++ (RT-PCR; NS) (14)+ (MA; NS) (15)++ (RT-PCR; NS) (16)+ (RT-PCR; C) (19)

PT (IHC) (49)PT (IHC) (50)PT (IHC) (51)

AP (IHC) (49)AP (IHC) (50)AP (IHC) (51)

rOat5

(SLC22A19)

+++ (RT-PCR; NS) (48) S2, S3 (IHC) (48) AP (48)

mOat5

(SLC22A19)

+++ (BDA; F; NS) (52)++ (BDA; M; NS) (52)

hPEPT1

(SLC15A1)

+ (RT-PCR; NS) (14)+ (MA; NS) (15)+ (RT-PCR; NS) (16)++ (RT-PCR; NS) (17)

rPept1

(Slc15a1)

+ (BDA; NS) (22)+ (BDA; NS) (23)- (BDA; NS) (24)++ (BDA; NS) (53)

S1 (PCR, ISH) (54)S1 (IHC) (55)

AP (IHC) (55)

mPept1

(Slc15a1)

- (BDA; NS) (53)

hPEPT2

(SLC15A2)

+ (RT-PCR; NS) (14)++ (MA; NS) (15)+ (RT-PCR; NS) (16)

PT (IHC) (56) AP (IHC) (56) rPept2

(Slc15a2)

++ (BDA; NS) (22)++ (BDA; NS) (23)- (BDA; NS) (24)+++ (BDA; NS) (53)

S3 (PCR, ISH) (54)S3 (IHC) (55)

AP (IHC) (55)

mPept2

(Slc15a2)

+++ (BDA; NS) (53)

hMATE1

(SLC47A1)

+++ (BDA; NS) (34) PT (IHC) (34)PT, DT (IHC) (57)

AP (IHC) (34)AP (IHC) (57)

rMate1

(Slc47a1)

++ (WB; NS) (58) PT (IHC) (58) AP (IHC) (58)

mMate1 6.35 fmol/ µg (MS; C) (31) b

1.37 fmol/ µg (MS; M) (31) b

PT, LoH, CD (IHC) (57)

AP (IHC) (57)

5

Human Rodent

Transporter(Gene)




Transporter(Gene)




(Slc47a1) +++ (BDA; NS) (59)

hMATE2-K

(SLC47A2)

+++ (BDA; NS) (34) PT (IHC) (34) AP (IHC) (34) mMate2

(Slc47a2)

- (BDA; NS) (59)

Key: +++ High; ++ Medium; + Low; - Absent or not quantified; NS Not specified; RT-PCR Real time polymerase chain reaction; WB Western Blot; IHC Immunohistochemistry; BDA Branched DNA assay; MA Microarray (hybridisation); MS liquid chromatography–tandem mass spectrometer (LC-MS/MS); ISH in situ hybridisation; K Whole kidney; C cortex; M medulla; OS outer stripe; G glomeruli, PT proximal tubule; S1/2/3 segment 1/2/3 of proximal tubule; TLH thin limb of loop of Henle, LoH Loop of Henle, TAL thick ascending limb of loop of Henle, DT distal tubule, CD collecting duct, BL basolateral membrane; AP brush-border (apical) membrane;

a Although an early study reported hOCT2 to be expressed at the apical membrane of distal tubule cells, the consensus opinion, based on subsequent studies, is that hOCT2 is expressed at the basolateral membrane of the proximal tubules (60); b Proteomics data per µg of plasma membrane protein (31); c Abundance per µg of total membrane protein (21)

6

3. Table S-II Table S-II. Expression of ABC Family Drug Transporters in the Human and Rodent Kidney

Human Rodent

Transporter(Gene)




Transporter(Gene)

KidneyAbundance(Method; Region)



hMDR1

(ABCB1)

++ (RT-PCR; NS) (14)++ (MA; NS) (15)++ (RT-PCR; NS) (16)+ (RT-PCR; NS) (17)++ (RT-PCR; NS) (61)

PT (IHC) (62)PT (IHC) (63)

AP (IHC) (62)AP (IHC) (63)

rMdr1a

(Abcb1a)

0.68 fmol/ µg (MS; K) (21) b

+ (BDA; NS) (22)- (BDA; NS) (23)- (BDA; NS) (24)++ (RT-PCR; NS) (61)

mMdr1a

(Abcb1a)

- (MS; C; M) (31) a

++ (RT-PCR; NS) (61)

rMdr1b

(Abcb1a)

+ (BDA; NS) (22)+ (BDA; NS) (23)- (BDA; NS) (24)++ (RT-PCR; NS) (61)

mMdr1b

(Abcb1a)

- (MS; C; M) (31) a

++ (RT-PCR; NS) (61)

hMRP1

(ABCC1)

+ (RT-PCR; NS) (14)++ (MA; NS) (15)+ (RT-PCR; NS) (16)- (RT-PCR; NS) (17)

G, DT, CD (IHC) (64) BL (64) rMrp1

(Abcc1)

+ (BDA; NS) (22)+ (BDA; NS) (23)- (BDA; NS) (24)

mMrp1

(Abcc1)

- (MS; C; M) (31) a

+ (WB; NS) (64)+ (BDA; NS) (65)

G, DT, CD (IHC) (64)TLH, CD (IHC) (66)

BL (IHC) (64)

hMRP2

(ABCC2)

++ (RT-PCR; NS) (14)++ (MA; NS) (15)++ (RT-PCR; NS) (16)- (RT-PCR; NS) (17)

PT (IHC) (67)PT (IHC) (68)PT (IHC) (69)

AP (IHC) (67)AP (IHC) (68)AP (IHC) (69)

rMrp2

(Abcc2)

++ (BDA; NS) (22)+ (BDA; NS) (23)- (BDA; NS) (24)

S1, S2, S3 (IHC) (70) AP (IHC) (70)

mMrp2

(Abcc2)

4.94 fmol/ µg (MS; C) (31) a

- (MS; M) (31) a

++ (BDA; NS) (65)

7

Human Rodent

Transporter(Gene)




Transporter(Gene)




hMRP3

(ABCC3)

+ (RT-PCR; NS) (14)++ (MA; NS) (15)+ (RT-PCR; NS) (16)-(RT-PCR; NS) (17)

TLH, CD (IHC) (71) rMrp3

(Abcc3)


PT (IHC) (72) BL (IHC) (72)

mMrp3

(Abcc3)

- (MS; C; M) (31) a

+ (BDA; NS) (65)+ (BDA; M; NS) (73)++ (BDA; F; NS) (73)

hMRP4

(ABCC4)

++ (RT-PCR; NS) (14)+ (MA; NS) (15)++ (RT-PCR; NS) (16)- (RT-PCR; NS) (17)+ (RT-PCR; NS) (61)

PT (IHC) (69) AP (IHC) (69) rMrp4

(Abcc4)

0.54 fmol/ µg (MS; K) (21) b

+ (BDA; NS) (22)+ (BDA; NS) (23)+ (BDA; NS) (24)+ (RT-PCR; NS) (61)

mMrp4

(Abcc4)

0.22 fmol/ µg (MS; M) (31) a

0.72 fmol/ µg (MS; C) (31) a

+ (BDA; M; NS) (65)++ (BDA; F; NS) (65)+ (RT-PCR; NS) (61)

hMRP5

(ABCC5)


rMrp5

(Abcc5)

+ (BDA; NS) (22)- (BDA; NS) (23)- (BDA; NS) (24)

mMrp5

(Abcc5)

- (MS; C; M) (31) a

+ (BDA; NS) (65)

hMRP6

(ABCC6)


PT (IHC) (68) BL (IHC) (68) rMrp6

(Abcc6)


mMrp6

(Abcc6)

- (MS; C; M) (31) a

- (BDA; NS) (24)+ (BDA; NS) (65)

8

Human Rodent

Transporter(Gene)




Transporter(Gene)




hBCRP

(ABCG2)

+ (RT-PCR; NS) (14)+ (MA; NS) (15)+ (RT-PCR; NS) (16)+ (RT-PCR; NS) (61)

PT (IHC) (61) BL (IHC) (61) rBCRP

(Abcg2)

15.9 fmol/ µg (MS; K) (21) b

+ (RT-PCR; NS) (61)

mBCRP

(Abcg2)

+ (RT-PCR; NS) (61)

Key: +++ High; ++ Medium; + Low; - Absent; NS Not specified; RT-PCR Real time polymerase chain reaction; IHC Immunohistochemistry; BDA Branched DNA assay; MA Microarray (hybridisation); MS liquid chromatography–tandem mass spectrometer; ISH in situ hybridisation; K Whole kidney; C cortex; M medulla; OS outer stripe; G glomeruli, PT proximal tubule; S1/2/3 segment 1/2/3 of proximal tubule; TLH thin limb of loop of Henle, DT distal tubule, CD collecting duct, BL basolateral membrane; AP brush-border (apical) membrane

a Abundance per µg of plasma membrane protein (31); b Abundance per µg of total membrane protein (21)

9

4. Table S-III Table S-III. Expression of OATP Family Drug Transporters n the Human and Rodent Kidney

Human Rodent

Transporter(Gene)




Transporter(Gene)




rOatp1a1

(Slco1a1)

+++ (BDA; NS) (22)- (BDA; NS) (23)+ (BDA; NS) (24)

S3 (IHC) (74) AP (IHC) (74)

mOatp1a1

(Slco1a1)

12.1 fmol/ µg (MS; C) (31) a

2.86 fmol/ µg (MS; M) (31) a

M>F (75)

hOATP1A2

(SLCO1A2)

+ (RT-PCR; NS) (14)- (MA; NS) (15)- (RT-PCR; NS) (16)- (RT-PCR; NS) (17)

DT (IHC) (76) AP (IHC) (76)

rOatp1a3

(Slco1a3)

+++ (BDA; NS) (22)+ (BDA; NS) (23)+++ (BDA; NS) (24)

rOatp1a4

(Slco1a4)


mOatp1a4

(Slco1a4)

- (MS; C; M) (31) a

rOatp1a5

(Slco1a5)


rOatp1a6

(Slco1a6)

+++ (BDA; NS) (22)+++ (BDA; NS) (23)+++ (BDA; NS) (24)

hOATP1B1 - (RT-PCR; NS) (14)- (MA; NS) (15)

10

Human Rodent

Transporter(Gene)




Transporter(Gene)




(SLCO1B1) - (RT-PCR; NS) (16)- (RT-PCR; NS) (17)

rOatp1b2

(Slco1b2)


hOATP1B3

(SLCO1B3)

+ (RT-PCR; NS) (14)- (MA; NS) (15)

hOATP1C1

(SLCO1C1)

+ (RT-PCR; NS) (14)- (MA; NS) (15)- (RT-PCR; NS) (16)

rOatp1c1

(Slco1c1)

- (MS; C; M) (31) a

hOATP2A1

(SLCO2A1)

++ (MA; NS) (15) rOatp2a1

(Slco2a1)

CD (IHC) (77)DT, CD (IHC) (78)

AP (IHC) (77)

hOATP2B1

(SLCO2B1)

+ (RT-PCR; NS) (14)+ (MA; NS) (15)+ (RT-PCR; NS) (16)+ (RT-PCR; NS) (17)

rOatp2b1

(Slco2b1)


hOATP3A1

(SLCO3A1)


rOatp3a1

(Slco3a1)

M>F (75) DT, CD (IHC) (78)

hOATP4A1

(SLCO4A1)

+ (RT-PCR; NS) (14)+ (MA; NS) (15)+ (RT-PCR; NS) (16)

rOatp4a1

(Slco4a1)

+ (BDA; NS)(22)+ (BDA; NS) (23)- (BDA; NS) (24)

hOATP4C1

(SLCO4C1)

++ (RT-PCR; NS) (14)+++ (MA; NS) (15)

rOatp4c1

(Slco4c1)

S1, S2, S3 (RT-PCR, IHC) (79)

BL (IHC) (79)

hOATP5A1

(SLCO5A1)

- (MA; NS) (15)- (RT-PCR; NS) (16)

rOatp5a1

(Slco5s1)

11

Human Rodent

Transporter(Gene)




Transporter(Gene)




hOATP6A1

(SLCO6A1)

rOatp6b1

(Slco6b1)

- (BDA; NS) (22)

Key: +++ High; ++ Medium; + Low; - Absent; NS Not specified; RT-PCR Real time polymerase chain reaction; IHC Immunohistochemistry; BDA Branched DNA assay; MA Microarray (hybridisation); ISH in situ hybridisation; K Whole kidney; C cortex; M medulla; OS outer stripe; S1/2/3 segment 1/2/3 of proximal tubule; DT distal tubule, CD collecting duct, BL basolateral membrane; AP brush-border (apical) membrane

a Proteomics data per µg of plasma membrane protein (31)

12

5. References for tables I and IV and figure 2 in main text

5.1 References for Table IProtein References

CYP3A5 (80-87)

CYP2D6 (86-90)

FMO1 (86, 87, 91-97)

ADH/ ALDH (87, 97-100)

CES2 (87, 97, 101-107)

AKR1A1 (87, 108-111)

UGT1A9 (86, 87, 97, 112-120)

UGT2B7 (86, 87, 97, 113, 114, 117-124)

GSTM3 (97, 125, 126)(87, 127-132)

GSTP1 (87, 125, 129-134)

MGST1/2/3 (87, 131, 135-137)

5.2 References for Table IV

Disease References

Autosomal dominant polycystic kidney disease (138, 139)

Acquired cystic kidney disease (140-143)

Hypertensive nephrosclerosis (144)

Chronic ischaemic renal disease (144, 145)

Chronic glomerulonephritis (1, 144, 146, 147)

Diabetic nephropathy (144, 147-151)

HIV-associated nephropathy (152)

CKD – aetiology unspecified/ mixed (153-156)

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calculating proximal tubule cell number10.1208... · web viewusing these two values as the minimum...

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