Integrin α1β1 and transforming growth factor-β1 play distinct roles in alport glomerular pathogenesis and serve as dual targets for metabolic therapy

Dominic E Cosgrove, Kathryn Rodgers, Daniel Meehan, Caroline Miller, Karen Bovard, Amy Gilroy, Humphrey Gardner, Victor Kotelianski, Phillip Gotwals, Aldo Amatucci, Raghu Kalluri

Research output: Contribution to journalArticle

150 Citations (Scopus)

Abstract

Alport syndrome is a genetic disorder resulting from mutations in type IV collagen genes. The defect results in pathological changes in kidney glomerular and inner-ear basement membranes. In the kidney, progressive glomerulonephritis culminates in tubulointerstitial fibrosis and death. Using gene knockout-mouse models, we demonstrate that two different pathways, one mediated by transforming growth factor (TGF)-β1 and the other by integrin α1β1, affect Alport glomerular pathogenesis in distinct ways. In Alport mice that are also null for integrin α1 expression, expansion of the mesangial matrix and podocyte foot process effacement are attenuated. The novel observation of normative laminin isoforms (laminin-2 and/or laminin-4) accumulating in the glomerular basement membrane of Alport mice is markedly reduced in the double knockouts. The second pathway, mediated by TGF-β1, was blocked using a soluble fusion protein comprising the extracellular domain of the TGF-β1 type II receptor. This inhibitor prevents focal thickening of the glomerular basement membrane, but does not prevent effacement of the podocyte foot processes. If both integrin α1β1 and TGF-β1 pathways are functionally inhibited, glomerular foot process and glomerular basement membrane morphology are primarily restored and renal function is markedly improved. These data suggest that integrin α1β1 and TGF-β1 may provide useful targets for a dual therapy aimed at slowing disease progression in Alport glomerulonephritis.

Original languageEnglish (US)
Pages (from-to)1649-1659
Number of pages11
JournalAmerican Journal of Pathology
Volume157
Issue number5
DOIs
StatePublished - Jan 1 2000

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Transforming Growth Factors
Integrins
Glomerular Basement Membrane
Laminin
Podocytes
Glomerulonephritis
Kidney
Hereditary Nephritis
Therapeutics
Gene Knockout Techniques
Inborn Genetic Diseases
Collagen Type IV
Inner Ear
Basement Membrane
Knockout Mice
Disease Progression
Foot
Protein Isoforms
Fibrosis
Observation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Integrin α1β1 and transforming growth factor-β1 play distinct roles in alport glomerular pathogenesis and serve as dual targets for metabolic therapy. / Cosgrove, Dominic E; Rodgers, Kathryn; Meehan, Daniel; Miller, Caroline; Bovard, Karen; Gilroy, Amy; Gardner, Humphrey; Kotelianski, Victor; Gotwals, Phillip; Amatucci, Aldo; Kalluri, Raghu.

In: American Journal of Pathology, Vol. 157, No. 5, 01.01.2000, p. 1649-1659.

Research output: Contribution to journalArticle

Cosgrove, DE, Rodgers, K, Meehan, D, Miller, C, Bovard, K, Gilroy, A, Gardner, H, Kotelianski, V, Gotwals, P, Amatucci, A & Kalluri, R 2000, 'Integrin α1β1 and transforming growth factor-β1 play distinct roles in alport glomerular pathogenesis and serve as dual targets for metabolic therapy', American Journal of Pathology, vol. 157, no. 5, pp. 1649-1659. https://doi.org/10.1016/S0002-9440(10)64802-X
Cosgrove, Dominic E ; Rodgers, Kathryn ; Meehan, Daniel ; Miller, Caroline ; Bovard, Karen ; Gilroy, Amy ; Gardner, Humphrey ; Kotelianski, Victor ; Gotwals, Phillip ; Amatucci, Aldo ; Kalluri, Raghu. / Integrin α1β1 and transforming growth factor-β1 play distinct roles in alport glomerular pathogenesis and serve as dual targets for metabolic therapy. In: American Journal of Pathology. 2000 ; Vol. 157, No. 5. pp. 1649-1659.
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