Advertisement

Targeting Pericyte Differentiation as a Strategy to Modulate Kidney Fibrosis in Diabetic Nephropathy

  • Benjamin D. Humphreys
    Correspondence
    Address reprint requests to Benjamin D. Humphreys, MD, PhD, Harvard Institutes of Medicine, Room 550, 4 Blackfan Circle, Boston, MA 02115
    Affiliations
    Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and Harvard Stem Cell Institute, Cambridge, Massachusetts
    Search for articles by this author

      Summary

      Pericytes are a heterogeneous group of extensively branched cells located in microvessels where they make focal contacts with endothelium. Pericytes stabilize blood vessels, regulate vascular tone, synthesize matrix, participate in repair, and serve as progenitor cells, among other functions. Recent work has highlighted the role of pericytes and pericyte-like cells in fibrosis, in which chronic injury triggers pericyte proliferation and differentiation into collagen-secretory, contractile myofibroblasts with migration away from vessels, causing microvascular rarefaction. In this review the developmental origins of kidney pericytes and perivascular fibroblasts are summarized, pericyte to myofibroblast transition in type I diabetic nephropathy is discussed, and the regulation of pericyte differentiation into myofibroblasts as a therapeutic target for treatment of diabetic nephropathy is described.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Seminars in Nephrology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Risdon R.A.
        • Sloper J.C.
        • De Wardener H.E.
        Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis.
        Lancet. 1968; 2: 363-366
        • Nath K.A.
        Tubulointerstitial changes as a major determinant in the progression of renal damage.
        Am J Kidney Dis. 1992; 20: 1-17
        • Katz A.
        • Caramori M.L.
        • Sisson-Ross S.
        • et al.
        An increase in the cell component of the cortical interstitium antedates interstitial fibrosis in type 1 diabetic patients.
        Kidney Int. 2002; 61: 2058-2066
        • Fioretto P.
        • Mauer M.
        • Brocco E.
        • et al.
        Patterns of renal injury in NIDDM patients with microalbuminuria.
        Diabetologia. 1996; 39: 1569-1576
        • Essawy M.
        • Soylemezoglu O.
        • Muchaneta-Kubara E.C.
        • et al.
        Myofibroblasts and the progression of diabetic nephropathy.
        Nephrol Dial Transplant. 1997; 12: 43-50
        • Basile D.P.
        Rarefaction of peritubular capillaries following ischemic acute renal failure: a potential factor predisposing to progressive nephropathy.
        Curr Opin Nephrol Hypertens. 2004; 13: 1-7
        • Fioretto P.
        • Steffes M.W.
        • Sutherland D.E.
        • et al.
        Reversal of lesions of diabetic nephropathy after pancreas transplantation.
        N Engl J Med. 1998; 339: 69-75
        • Diaz-Flores L.
        • Gutierrez R.
        • Madrid J.F.
        • et al.
        Pericytes.
        Histol Histopathol. 2009; 24: 909-969
        • Courtnoy P.
        • Boyles J.
        Fibronectin in the microvasculature: localization in the pericyte-endothelial interstitium.
        J Ultrastruct Res. 1983; 83: 258-273
        • Rouget C.
        Memoire sur le developpement, la structure et les proprietes physiologiques des capillaries sanguins et lymphatiques.
        Arch Physiol Norm Pathol. 1873; 5: 603-663
        • Zimmerman K.
        Der feinere bau der blutcapillaren.
        Z Anat Entwicklungsgeschichte. 1923; 68: 29-36
        • Takahashi-Iwanaga H.
        The three-dimensional cytoarchitecture of the interstitial tissue in the rat kidney.
        Cell Tissue Res. 1991; 264: 269-281
        • Fujimoto K.
        Pericyte-endothelial gap junctions in developing rat cerebral capillaries: a fine structural study.
        Anat Rec. 1995; 242: 562-565
        • Kaissling B.
        • Hegyi I.
        • Loffing J.
        • et al.
        Morphology of interstitial cells in the healthy kidney.
        Anat Embryol (Berl). 1996; 193: 303-318
        • Kriz W.
        • Kaissling B.
        • Le Hir M.
        Epithelial-mesenchymal transition (EMT) in kidney fibrosis: fact or fantasy?.
        J Clin Invest. 2011; 121: 468-474
        • Asada N.
        • Takase M.
        • Nakamura J.
        • et al.
        Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice.
        J Clin Invest. 2011; 121: 3981-3990
        • Park F.
        • Mattson D.L.
        • Roberts L.A.
        • et al.
        Evidence for the presence of smooth muscle alpha-actin within pericytes of the renal medulla.
        Am J Physiol. 1997; 273: R1742-R1748
        • Pallone T.L.
        • Silldorff E.P.
        Pericyte regulation of renal medullary blood flow.
        Exp Nephrol. 2001; 9: 165-170
        • Crisan M.
        • Yap S.
        • Casteilla L.
        • et al.
        A perivascular origin for mesenchymal stem cells in multiple human organs.
        Cell Stem Cell. 2008; 3: 301-313
        • Goritz C.
        • Dias D.O.
        • Tomilin N.
        • et al.
        A pericyte origin of spinal cord scar tissue.
        Science. 2011; 333: 238-242
        • Nehls V.
        • Drenckhahn D.
        Heterogeneity of microvascular pericytes for smooth muscle type alpha-actin.
        J Cell Biol. 1991; 113: 147-154
        • Lin S.L.
        • Kisseleva T.
        • Brenner D.A.
        • et al.
        Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney.
        Am J Pathol. 2008; 173: 1617-1627
        • Sundberg C.
        • Ljungstrom M.
        • Lindmark G.
        • et al.
        Microvascular pericytes express platelet-derived growth factor-beta receptors in human healing wounds and colorectal adenocarcinoma.
        Am J Pathol. 1993; 143: 1377-1388
        • Eyden B.
        The myofibroblast: a study of normal, reactive and neoplastic tissues, with an emphasis on ultrastructure.
        J Submicrosc Cytol Pathol. 2005; 37: 231-296
        • Gabbiani G.
        The cellular derivation and the life span of the myofibroblast.
        Pathol Res Pract. 1996; 192: 708-711
        • Rajkumar V.S.
        • Howell K.
        • Csiszar K.
        • et al.
        Shared expression of phenotypic markers in systemic sclerosis indicates a convergence of pericytes and fibroblasts to a myofibroblast lineage in fibrosis.
        Arthritis Res Ther. 2005; 7: R1113-R1123
        • Zeisberg M.
        • Neilson E.G.
        Biomarkers for epithelial-mesenchymal transitions.
        J Clin Invest. 2009; 119: 1429-1437
        • Humphreys B.D.
        • Lin S.L.
        • Kobayashi A.
        • et al.
        Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis.
        Am J Pathol. 2010; 176: 85-97
        • Grgic I.
        • Duffield J.S.
        • Humphreys B.D.
        The origin of interstitial myofibroblasts in chronic kidney disease.
        Pediatr Nephrol. 2012; 27: 183-193
        • Zeisberg E.M.
        • Potenta S.E.
        • Sugimoto H.
        • et al.
        Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition.
        J Am Soc Nephrol. 2008; 19: 2282-2287
        • Rock J.R.
        • Barkauskas C.E.
        • Cronce M.J.
        • et al.
        Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition.
        Proc Natl Acad Sci U S A. 2011; 108: E1475-E1483
        • Ingham P.W.
        • McMahon A.P.
        Hedgehog signaling in animal development: paradigms and principles.
        Genes Dev. 2001; 15: 3059-3087
        • Mao J.
        • Kim B.M.
        • Rajurkar M.
        • et al.
        Hedgehog signaling controls mesenchymal growth in the developing mammalian digestive tract.
        Development. 2010; 137: 1721-1729
        • Yu J.
        • Carroll T.J.
        • McMahon A.P.
        Sonic hedgehog regulates proliferation and differentiation of mesenchymal cells in the mouse metanephric kidney.
        Development. 2002; 129: 5301-5312
        • Cain J.E.
        • Rosenblum N.D.
        Control of mammalian kidney development by the Hedgehog signaling pathway.
        Pediatr Nephrol. 2011; 26: 1365-1371
        • Hu M.C.
        • Mo R.
        • Bhella S.
        • et al.
        GLI3-dependent transcriptional repression of Gli1, Gli2 and kidney patterning genes disrupts renal morphogenesis.
        Development. 2006; 133: 569-578
        • Sasaki H.
        • Nishizaki Y.
        • Hui C.
        • et al.
        Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling.
        Development. 1999; 126: 3915-3924
        • Tian H.
        • Callahan C.A.
        • DuPree K.J.
        • et al.
        Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis.
        Proc Natl Acad Sci U S A. 2009; 106: 4254-4259
        • Yauch R.L.
        • Gould S.E.
        • Scales S.J.
        • et al.
        A paracrine requirement for hedgehog signalling in cancer.
        Nature. 2008; 455: 406-410
        • Olive K.P.
        • Jacobetz M.A.
        • Davidson C.J.
        • et al.
        Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer.
        Science. 2009; 324: 1457-1461
        • Shin K.
        • Lee J.
        • Guo N.
        • et al.
        Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder.
        Nature. 2011; 472: 110-114
        • Omenetti A.
        • Porrello A.
        • Jung Y.
        • et al.
        Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans.
        J Clin Invest. 2008; 118: 3331-3342
        • Syn W.K.
        • Choi S.S.
        • Liaskou E.
        • et al.
        Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis.
        Hepatology. 2011; 53: 106-115
        • Choi S.S.
        • Omenetti A.
        • Witek R.P.
        • et al.
        Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis.
        Am J Physiol Gastrointest Liver Physiol. 2009; 297: G1093-G1106
        • Stewart G.A.
        • Hoyne G.F.
        • Ahmad S.A.
        • et al.
        Expression of the developmental Sonic hedgehog (Shh) signalling pathway is up-regulated in chronic lung fibrosis and the Shh receptor patched 1 is present in circulating T lymphocytes.
        J Pathol. 2003; 199: 488-495
        • Fabian S.L.
        • Penchev R.R.
        • St-Jacques B.
        • et al.
        Hedgehog-Gli pathway activation during kidney fibrosis.
        Am J Pathol. 2012; 180: 1441-1453
        • Tremblay M.R.
        • Lescarbeau A.
        • Grogan M.J.
        • et al.
        Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926).
        J Med Chem. 2009; 52: 4400-4418
        • Ziyadeh F.N.
        • Sharma K.
        Overview: combating diabetic nephropathy.
        J Am Soc Nephrol. 2003; 14: 1355-1357
        • Zhu Y.
        • Usui H.K.
        • Sharma K.
        Regulation of transforming growth factor beta in diabetic nephropathy: implications for treatment.
        Semin Nephrol. 2007; 27: 153-160
        • Yamamoto T.
        • Nakamura T.
        • Noble N.A.
        • et al.
        Expression of transforming growth factor beta is elevated in human and experimental diabetic nephropathy.
        Proc Natl Acad Sci U S A. 1993; 90: 1814-1818
        • Sakharova O.V.
        • Taal M.W.
        • Brenner B.M.
        Pathogenesis of diabetic nephropathy: focus on transforming growth factor-beta and connective tissue growth factor.
        Curr Opin Nephrol Hypertens. 2001; 10: 727-738
        • Kopp J.B.
        • Factor V.M.
        • Mozes M.
        • et al.
        Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease.
        Lab Invest. 1996; 74: 991-1003
        • Ledbetter S.
        • Kurtzberg L.
        • Doyle S.
        • et al.
        Renal fibrosis in mice treated with human recombinant transforming growth factor-beta2.
        Kidney Int. 2000; 58: 2367-2376
        • Border W.A.
        • Okuda S.
        • Languino L.R.
        • et al.
        Suppression of experimental glomerulonephritis by antiserum against transforming growth factor β1.
        Nature. 1990; 346: 371-374
        • Kasuga H.
        • Ito Y.
        • Sakamoto S.
        • et al.
        Effects of anti-TGF-beta type II receptor antibody on experimental glomerulonephritis.
        Kidney Int. 2001; 60: 1745-1755
        • Zimmerman B.J.
        • Holt J.W.
        • Paulson J.C.
        • et al.
        Molecular determinants of lipid mediator-induced leukocyte adherence and emigration in rat mesenteric venules.
        Am J Physiol. 1994; 266: H847-H853
        • Sato M.
        • Muragaki Y.
        • Saika S.
        • et al.
        Targeted disruption of TGF-beta1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction.
        J Clin Invest. 2003; 112: 1486-1494
        • Inazaki K.
        • Kanamaru Y.
        • Kojima Y.
        • et al.
        Smad3 deficiency attenuates renal fibrosis, inflammation, and apoptosis after unilateral ureteral obstruction.
        Kidney Int. 2004; 66: 597-604
        • Burns W.C.
        • Twigg S.M.
        • Forbes J.M.
        • et al.
        Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease.
        J Am Soc Nephrol. 2006; 17: 2484-2494
        • Hills C.E.
        • Squires P.E.
        TGF-beta1-induced epithelial-to-mesenchymal transition and therapeutic intervention in diabetic nephropathy.
        Am J Nephrol. 2010; 31: 68-74
        • Bielesz B.
        • Sirin Y.
        • Si H.
        • et al.
        Epithelial Notch signaling regulates interstitial fibrosis development in the kidneys of mice and humans.
        J Clin Invest. 2010; 120: 4040-4054
        • Endo T.
        • Okuda T.
        • Nakamura J.
        • et al.
        Exploring the origin of the cells responsible for regeneration and fibrosis in the kidneys [abstract].
        J Am Soc Nephrol. 2010; 21: 36A
        • Koesters R.
        • Kaissling B.
        • Lehir M.
        • et al.
        Tubular overexpression of transforming growth factor-beta1 induces autophagy and fibrosis but not mesenchymal transition of renal epithelial cells.
        Am J Pathol. 2010; 177: 632-643
        • Fraser D.
        • Brunskill N.
        • Ito T.
        • et al.
        Long-term exposure of proximal tubular epithelial cells to glucose induces transforming growth factor-beta 1 synthesis via an autocrine PDGF loop.
        Am J Pathol. 2003; 163: 2565-2574
        • Zhang M.
        • Fraser D.
        • Phillips A.
        ERK, p38, and Smad signaling pathways differentially regulate transforming growth factor-beta1 autoinduction in proximal tubular epithelial cells.
        Am J Pathol. 2006; 169: 1282-1293
        • Yang L.
        • Besschetnova T.Y.
        • Brooks C.R.
        • et al.
        Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury.
        Nat Med. 2010; 16 (1p following 143): 535-543
        • Van Geest R.J.
        • Klaassen I.
        • Vogels I.M.
        • et al.
        Differential TGF-{beta} signaling in retinal vascular cells: a role in diabetic retinopathy?.
        Invest Ophthalmol Vis Sci. 2010; 51: 1857-1865
        • Strutz F.
        • Zeisberg M.
        • Renziehausen A.
        • et al.
        TGF-beta 1 induces proliferation in human renal fibroblasts via induction of basic fibroblast growth factor (FGF-2).
        Kidney Int. 2001; 59: 579-592
        • Strutz F.
        • Zeisberg M.
        • Hemmerlein B.
        • et al.
        Basic fibroblast growth factor expression is increased in human renal fibrogenesis and may mediate autocrine fibroblast proliferation.
        Kidney Int. 2000; 57: 1521-1538
        • Vasko R.
        • Koziolek M.
        • Ikehata M.
        • et al.
        Role of basic fibroblast growth factor (FGF-2) in diabetic nephropathy and mechanisms of its induction by hyperglycemia in human renal fibroblasts.
        Am J Physiol. 2009; 296: F1452-F1463
        • Floege J.
        • Eitner F.
        • Alpers C.E.
        A new look at platelet-derived growth factor in renal disease.
        J Am Soc Nephrol. 2008; 19: 12-23
        • Lassila M.
        • Jandeleit-Dahm K.
        • Seah K.K.
        • et al.
        Imatinib attenuates diabetic nephropathy in apolipoprotein E-knockout mice.
        J Am Soc Nephrol. 2005; 16: 363-373
        • Chen Y.T.
        • Chang F.C.
        • Wu C.F.
        • et al.
        Platelet-derived growth factor receptor signaling activates pericyte-myofibroblast transition in obstructive and post-ischemic kidney fibrosis.
        Kidney Int. 2011; 80: 1170-1181
        • Chen Y.
        • Abraham D.J.
        • Shi-Wen X.
        • et al.
        CCN2 (connective tissue growth factor) promotes fibroblast adhesion to fibronectin.
        Mol Biol Cell. 2004; 15: 5635-5646
        • Abraham S.
        • Kogata N.
        • Fassler R.
        • et al.
        Integrin beta1 subunit controls mural cell adhesion, spreading, and blood vessel wall stability.
        Circ Res. 2008; 102: 562-570
        • van Nieuwenhoven F.A.
        • Jensen L.J.
        • Flyvbjerg A.
        • et al.
        Imbalance of growth factor signalling in diabetic kidney disease: is connective tissue growth factor (CTGF, CCN2) the perfect intervention point?.
        Nephrol Dial Transplant. 2005; 20: 6-10
        • Nguyen T.Q.
        • Tarnow L.
        • Andersen S.
        • et al.
        Urinary connective tissue growth factor excretion correlates with clinical markers of renal disease in a large population of type 1 diabetic patients with diabetic nephropathy.
        Diabetes Care. 2006; 29: 83-88
        • Nguyen T.Q.
        • Tarnow L.
        • Jorsal A.
        • et al.
        Plasma connective tissue growth factor is an independent predictor of end-stage renal disease and mortality in type 1 diabetic nephropathy.
        Diabetes Care. 2008; 31: 1177-1182
        • Ponticos M.
        • Holmes A.M.
        • Shi-wen X.
        • et al.
        Pivotal role of connective tissue growth factor in lung fibrosis: MAPK-dependent transcriptional activation of type I collagen.
        Arthritis Rheum. 2009; 60: 2142-2155
        • Liu S.
        • Shi-wen X.
        • Abraham D.J.
        • et al.
        CCN2 is required for bleomycin-induced skin fibrosis in mice.
        Arthritis Rheum. 2011; 63: 239-246
        • Adler S.G.
        • Schwartz S.
        • Williams M.E.
        • et al.
        Phase 1 study of anti-CTGF monoclonal antibody in patients with diabetes and microalbuminuria.
        Clin J Am Soc Nephrol. 2010; 5: 1420-1428