The McCarthy laboratory was awarded two US patents in 2019.  

2019 Kevin McCarthy and Deborah McCarthy were recently awarded a US Patent entitled "Hybrid linear actuator controlled hydraulic cell stretching apparatus" for the development of a novel device capable of growing cells under controlled, cyclic stretch conditions.

2019 Kevin McCarthy and Gulshan Sunavala DDS, PhD were recently awarded a US Patent entitled “Overload Failure Reducing Dental Implants” for the development of a dental implant that absorbs occlusive loading that occurs during mastication. 

The projects were developed and tested using 3D modeling and printing in the McCarthy laboratory.  The McCarthy laboratory uses Maxon Cinema 4D™ for 3D modeling and Airwolf™ 3D printers for prototyping.

The Beginning of the End of the Road for a Renal Glomerulus

The images shown below are sections of kidney taken from age-matched non-diabetic control animals and type II diabetic animals (18 weeks duration). The central figure in both images is a renal glomerulus. The sections were immunostained with antibodies directed against syndecan-4 (green,  monoclonal antibody to the ectodomain of the syndecan-4 core protein) and alpha-actinin-4 (red). In the control animals, both syndecan-4 and alpha-actinin-4 co-distribute along the walls of the glomerular capillaries, the pattern of staining having the appearance of punctate along the length of the perimeter of the glomerular capillary wall. .  In the diabetic animal, the pattern of syndecan-4 staining is disrupted, as indicated by the loss of the green signal.   We believe this is due to the disengagement of the interactions between Syndecan-4 with its ligands in the glomerular capillary wall.  The narrative below provides further background information.

The Epidemic of Chronic Kidney Disease

Chronic Kidney Disease (CKD) can be the result of several underlying disease processes, such as poorly controlled hypertension or diabetes mellitus.  In some individuals, acceleration of the progression towards the final stages of CKD can occur when two or more co-morbidities exist in an individual (e.g. a hypertensive diabetic).  According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK),  14% of the general population ( approx 46 million people) has some form/stage of CKD.  In 2015, NIDDK reported that 661,000 people had entered into renal failure, of these 468,000 were on hemodialysis.  The current cost for treating people over the age of 65 for CKD was greater than $50 billion dollars in 2013 according to a current NIDDK report. 

A key contributor to the development of CKD is underlying metabolic disease, such as diabetes mellitus.  According to data from the American Diabetes Association, in 2015  9.4% of the US population (approx 30 million people) had diabetes mellitus, with 1.5 million new cases being diagnosed every year.   This was not always the case and one has to wonder where things started taking a turn for the worse.  From a look back in time, according to the Center for Disease Control data, in 1960 there were only 1.59 million people (0.91% of the population) that were diagnosed as having diabetes mellitus.  The fact that there has been a proportionate 10-fold increase of diabetes in our population since 1960 is nothing short of disconcerting.   If the trend continues, the economic burden in treating the complications arising from long term diabetes mellitus will be staggering.

Early Studies in Diabetic Nephropathy in the McCarthy Lab

The research direction of the laboratory towards studying the effects of CKD on the renal glomerulus was initially set by a serendipitous (i.e. lucky) observation.   We had found that an antibody, directed against a basement membrane chondroitin sulfate proteoglycan, specifically stained the extracellular matrix present in glomerular mesangium and not the matrix comprising the glomerular basement membrane (J Cell Biol. 109:  3187-3198).  A subsequent study showed that the pattern of staining of this antibody was highly regulated during the development of the kidney (J. Histochem. Cytochem 41: 401-414).  Interestingly and germane to kidney disease, we found that the pattern of immunostaining of this antibody in the kidney was a very good marker that demonstrated the progression of CKD in a model of diabetic kidney disease.   The pattern of antibody staining readily identified the initiation of the process of mesangial expansion in the glomeruli of diabetic animals (J Histochem Cytochem  42: 473-484) which is considered to be an indicator of the eventual demise of the glomerular structure and ultimately kidney function (Diabetes 38:1077-81).   The logical follow-up study was to determine if early intervention in an animal model of type II diabetes via the correction of blood glucose levels with the thiazolidinedione, troglitazone, could prevent mesangial expansion from occurring (Kidney International 58: 2341-2350).   The results of that study were extremely positive and showed that earlier intervention with thiazolidinedione treatment prevented the development of mesangial expansion from occurring.

A Slight Detour Leads to a Novel Observation

Within the field of renal biology, it had been understood from studies done in the last millenium that the extracellular matrix which forms the glomerular capilliary wall contributes, in part, to the ultrafiltration barrier function of the glomerular capillary wall  (Microscopy and Microanalysis 18:3-21).   Key components of the glomerular capillary extracelllar matrix, heparan sulfate proteoglycans (agrin and perlecan), were thought to limit the diffusion of proteins from the bloodstream into the urinary space, due to the net anionic charge density presented by the heparan sulfate glycosaminoglycan chains attached to these proteins.   This hypothesis has been explored and tested by several groups over the past forty years; the results of those studies more often than not contributed to further debate about the actual process of ultrafiltration.   

Although the focus of our work for years had been on studying how the proteoglycans made by mesangial cells were affected by underlying diabetic nephropathy, an opportunity presented itself where we could develop an animal model that would allow us to explore the role of heparan sulfate glycosaminoglycan in glomerular ultrafiltration.   Through the development of this novel mouse model, we thought we could address the nagging questions raised by numerous investigators with regard to the role of heparan sulfate proteoglycans/ glycosaminoglycans in glomerular ultrafiltration.   The mouse model was made by breeding a podocyte-specific Cre expressing mouse (Genesis 35: 39-42) with a recently-developed Ext1fl/fl mouse (Science 302, 1044–1046) we developed a mouse model in which glomerular podocytes are unable to assemble heparan sulfate glycosaminoglycans on all heparan sulfate proteoglycan core proteins (Kidney International 74: 289-299).   

Serendipity (i.e. luck) again decided to visit the laboratory.   Our hypothesis, at the time that we began our studies, was based on the conventional wisdom that existed in the field of glomerular biology.   We had hypothesized that the resulting mutant mouse from our animal breeding scheme should develop severe proteinuria within a few weeks after birth.   As mentioned in the paragraph above, our hypothesis was based on an existing concept in the renal field that heparan sulfate glycosaminoglycans in the glomerular basement membrane contributed to the charge selectivity of the glomerular ultrafiltration barrier.  Thus, by removing the majority of heparan sulfate glycosaminglycans in the glomerular basement membrane via the genetic manipulation in our mutant mouse model, we postulated that the mouse should develop severe proteinuria as the kidneys began handling the ultrafiltration load for the animal after birth.   They didn't.   In fact the mutant mouse model (the PEXTKO mouse, Kidney International 74: 289-299) ended up living a normal lifespan and does not develop any significant degree of proteinuria.   As we began to characterize the phenotype of PEXTKO mouse we discovered that despite the lack of proteinuria, the glomerular podocytes developed what is known as pedicel or "foot process" effacement-i.e. a complete disruption of the normal interactions that occur between the glomerular podocyte and the glomerular basement membrane.  Foot process or pedical effacement is seen in many renal diseases, such as diabetic nephropathy.   Based on our earlier work, we used morphometry to investigate whether or not the glomeruli in the PEXTKO mouse developed mesangial expansion during the course of their lifespan.  Although we found that the glomeruli in the PEXTKO mouse developed hypertrophy, the mesangium itself remained unchanged relative to the overall size of the glomerulus.

The pedicel effacement did suggest the possibility that the podocytes in the mutant animals did suffer from an adhesion defect, mediated by the lack of heparan sulfate glycosaminoglycan chains on the core proteins of cell surface proteoglycans.   To test this hypothesis, we developed immortalized podocyte cell lines that were able to synthesize heparan sulfate glycosaminoglycan chains or unable to synthesize heparan sulfate glycosaminoglycan chains ( Kidney International 78:1088-1099). We tested the cells via standard cell adhesion and migration assays and demonstrated that the HS- podocytes were inefficient with regard to attachment to a matrix substrate (fibronectin) and migrated poorly on the substrate compared to wild-type (HS+) podocytes.   Immunostaining for the cell surface proteoglycan, Syndecan-4,  and cytoskeletal components showed that HS- podocytes had profound differences in their ability to organize focal adhesions and their cytoskeletal organization compared to HS+ podocytes.   Immunostaining for Syndecan-4 in renal tissue sections from the PEXTKO mouse showed that the pattern of immunostaining for Syndecan-4 was disrupted in the renal glomerulus compared to control animals, the disruption similar to that seen in the glomerulus shown above, taken from the diabetic animal.

Based on the data derived from the PEXTKO mouse and our in vitro studies using the HS+ and HS- podocytes, we proposed a basic model  of how changes to the structure (sulfation, epimerization) of HS (heparan sulfate glycosaminoglycan) that is assembled posttranslationally on Syndecan core proteins present on the basal surfaces of podocyte pedicels affect pedicel organization along the length of the GBM. 

In normal conditions, Syndecans (shown in blue/red) are capable of engaging matrix glycoproteins present in the glomerular basement membrane via the pattern of sulfation present on the HS chains (shown in red).   The interaction between HS chains and matrix glycoproteins is somewhat promiscuous, since HS is capable of having many different binding partners.  Syndecans work alongside integrins (shown in green/yelllow), which are cell surface matrix receptors that have a rather high degree of specificity.   The syndecan-integrin pairing promotes the development of a normal adhesive phenotype and normal cytoskeletal organization for the podocyte pedicel.   When either the ability to assemble HS chains is lost, as in our PEXTKO model or in our more recent Ndst1-null mouse model (Kidney International 85: 307-3018), these changes to the post-assembly modifications of HS render syndecans incapable of efficient interactions with matrix glycoproteins.  In vitro, using our latest model, the Ndst1 null mouse, we were able to show that podocytes are unable to efficiently adhere and migrate on extracullar matrices, the integrin activation status is downregulated (American Journal of Physiology, Renal Physiology 310: F1123-F1135).

A third alternative, that we are currently testing, is that conditions present in diabetes lead to the enhanced shedding of Syndecans from the basal surface of the podoctye pedicel.   We believe that the loss of the Syndecan-basement membrane interaction, by whatever means,  is associated with foot process effacement in vivo and disruption of the pattern of staining for podocyte syndecan in the glomerulus. 

How are these mutant mouse studies relevant to the human condition?

The PEXTKO mouse model (podocytes lack the ability to assemble HS) gave some insight, albeit an extreme model, as to how important the HS on Syndecans is with regard to the maintenance of normal podocyte architecture.   The Ndst1-null mouse model (Kidney International 85: 307-3018, American Journal of Physiology, Renal Physiology 310: F1123-F1135) represents a refined model that more closely reflects what is seen in the glomeruli of diabetic animal models.  Ndst1 is an enzyme responsible for the N-sulfation of N-acetylglucosamine residues on HS.   In turn, when this activity is removed from cells via genetic manipulation, the HS made by the cells is known to be undersulfated.   Expression data from genomic screening studies in humans have shown that in humans the overall expression of Ndst1 is significantly decreased in the glomeruli isolated from kidney samples taken from diabetic individuals.  We believe that conditions present in diabetes mellitus forces the decrease in expression of Ndst1 which, in turn, would ultimately compromise the ability of podocytes to properly N-sulfate the heparan sulfate present on Syndecans.   This would contribute in part, to the foot process effacement that does develop in the glomeruli of diabetic animals. 

A key question remains to be answered............

The results of our work with the PEXTKO mutant mice would suggest that the role of HS in ultrafiltration is minimal, at best.  However, in our original report (Kidney International 74: 289-299) we noted that at 6 months of age the presence of large lysosomes developing in the proximal tubule epithelial cells, these lysosomes persisting throughout the life of the PEXTKO mice.  This would suggest that the loss of HS in the glomerular basement membrane (and podocyte pedicels) had some effect on ultrafiltration, but the net effect could have been masked by an enhanced protein recovery in the proximal tubule epithelial cells (Kidney International 71: 504-513; JASN 27: 482-494).

In order to answer that question, we tried to use an Intravital Two-Photon Microscopy approach to determine to what degree ultrafiltration had been affected in our PEXTKO mutant mouse models  (Kidney International 71: 504-513; JASN 27: 482-494).  After taking a course on intravital Two-Photon Microscopy at the IUPUI Research Center for Quantitative Renal Imaging we began our studies exploring the possible differences in renal ultrafiltration between wild-type and PEXTKO mice.  

Selected Publications

1. McCarthy KJ, MA Accavitti, and JR Couchman(1989)   Immunological characterization of a basement membrane specific chondroitin sulfate proteoglycan.   J Cell Biol. 109:  3187-3198.
2. McCarthy KJ and GI Kaye (1990).  Comparison of osmium/sonication and EDTA sonication microdissection techniques in exposing the adepithelial basal lamina surface of developing rat colon.  J. EM. Tech.  14:  367-372.
3. McCarthy KJ and JR Couchman (1990 )  Basement membrane specific chondroitin sulfate proteoglycans: localization in adult rat tissues.  J. Histochem. Cytochem 38:  1479-1486.
4. Couchman JR,  JL King, and KJ McCarthy (1990).  Distribution of two basement membrane proteoglycans through hair follicle development and  hair growth cycle in the rat.  J. Invest. Dermatol., 94:  65-70.
5. Yoshizuka M, KJ McCarthy, GI Kaye, and S Fujimoto (1990).  Cadmium  toxicity to the cornea of pregnant rats:  Electron microscopy and X-ray microanalysis.  Anat. Rec. 227:  138-143.
6. McCarthy KJ,  Y Horiguchi, JR Couchman, and J-D Fine (1990).  Ultrastructural localization of the core protein of a basement membrane -specific  chondroitin sulfate proteoglycan in adult rat skin.  Arch. of Dermatol. Res. 282:  397-401.
7. Couchman JR, KJ McCarthy, DR Abrahamson, J-D Fine, and GR Parry (1990).  Immunological and molecular approaches to the study of basement membrane proteoglycan diversity.  Biochem. Soc. Transactions 18:  819-820.
8. Lyons AW, S Narindrasorasak, ID Young, T Anastassiades, JR Couchman, KJ McCarthy, and R Kisilevsky (1991).  Co-deposition of basement membrane components during induction of murine splenic AA amyloid.  Lab. Invest. 64:  785-790.
9. Lin WL, E Essner, KJ McCarthy, and JR Couchman (1992).  Ultrastructural immunocytochemical localization of chondroitin sulfate proteoglycan in Bruch’s membrane of the rat.  Invest. Opthal. Vis. Science 33:  2072-2075
10. Couchman JR, KJ McCarthy , and A Woods (1992).  Proteoglycans and glycoproteins in hair follicle development and cycling.  In “The Structure and Molecular Biology of Hair” K. S. Stein, A.G. Messenger, H. P. Baden, eds.  Annals of the New York Academy of Sciences vol. 642,  The New York Academy of Sciences, New York. pp 243-252.
11. McCarthy KJ, JR Couchman, DR Abrahamson, K. Bynum, and PL St John (1994).  Basement membrane specific chondroitin sulfate proteoglycan is abnormally associated with the glomerular capillary basement membrane in diabetic rats.  J Histochem Cytochem  42: 473-484.
12. Couchman JR, DR Abrahamson, and KJ McCarthy (1993)  Basement membrane proteoglycans and development.  Kidney Int. 39: 79-84 (review).
13. McCarthy KJ, K. Bynum, PL St. John, DR Abrahamson , and JR Couchman (1993).  Basement membrane proteoglycans in glomerular morphogenesis:  Chondroitin sulfate proteoglycan is temporally and spatially restricted during development.  J. Histochem. Cytochem 41: 401-414.
14. Lipke DW, KJ McCarthy, TS Elton, SS Arcot, S Oparil, and JR Couchman (1993).  Coarctation induces alterations in basement membranes in the cardiovascular system.  Hypertension 22:  743-753
15. Ehara T, FA Carone, KJ McCarthy, and JR Couchman (1994).  Basement membrane chondroitin sulfate proteoglycan alterations in a rat model of polycystic kidney disease.  AM. J. Path. 144: 612-621.
16. Sannes PL, KK Burch, J Khosla, KJ McCarthy, and JR Couchman (1993).  Immunohistochemical localization of chondroitin sulfate, chondroitin sulfate proteoglycan, entactin, and laminin in basement membranes of postnatal developing and adult rat lungs.  Am. J. Resp. Cell and Mol. Biol. 8:  245-251.
17. Couchman JR, LA Beavan, and KJ McCarthy (1994).  Glomerular Matrix:  Synthesis, turnover, and role in mesangial expansion.  Kidney Int 45: 328-335.
18. McAndrew J, AJ Paterson, SL Asa, KJ McCarthy, and JE Kudlow (1995).  Targeting of transforming growth factor-a expression to pituitary lactotrophs in transgenic mice results in selective lactotroph proliferation and adenomas.  Endocrinology 136:  4479-4488
19. Thomas, G, L Shewring, KJ McCarthy, JR Couchman, RM Mason, and M Davies (1995).  Rat mesangial cells in vitro  synthesize a spectrum of proteoglycan species including those of the basement membrane and interstitium.  Kidney International 48:  1278-1289.
20. McCarthy KJ (1997)  Development of the glomerular basement membrane and mesangial matrix:  Asynchronous maturation of glomerular extracellular matrices.  Microscopy Research and Technique 39: 233-253
21. Wassenhove-McCarthy DJ and KJ McCarthy (1999).  Molecular characterization of a novel basement membrane associated proteoglycan, leprecan.  J. Biol. Chem. 274: 25004-25017.
22. Rayan, G.M., C.J. Haaksma, J.J. Tomasek,, and K.J. McCarthy (2000) Basement membrane chondroitin sulfate proteoglycan and vascularization of the developing mammalian limb bud.  Journal of Hand Surgery 25: 150-158.
23. Kolomytkin OV, A A Marino, KK Sadasivan, WD. Meek, Robert E. Wolf, V Hall, KJ McCarthy, and J A Albright (2000).  Gap junctions in human synovial cells and tissue.  Journal of Cellular Physiology. 184: 110-117.
24. McCarthy KJ, RE Routh, W Shaw, K Walsh, TC Wellbourne, and JH Johnson (2000).  Troglitazone halts diabetic glomerulosclerosis by blockade of mesangial expansion.  Kidney International 58: 2341-2350.
25. Bhatti, R, DP Mukerjee, KJ McCarthy, SH Rogers, DF Smith, and SW Shalaby (2001).  The growth of chondrocytes into a fibronectin-coated biodegradable scaffold.  J. Biomaterials Research, 56:74-82.
26. Routh, RE, JH Johnson, and KJ McCarthy (2002). Troglitazone suppresses the secretion of type I collagen by mesangial cells in vitro. Kidney International 61:1365-1376.
27. Lauer, M and KJ McCarthy (2002).  In vitro matrix assembly induced by the Critical Assembly Concentration.  J. Histochem. Cytochem, 50: 1537-1541.
28. Routh RE, KJ McCarthy, and TC Welbourne (2002). Troglitazone inhibits glutamine metabolism in cultured rat mesangial cells. Am J Physiol Endocrinol Metab 282: E231-238.
29. T. Welbourne, G. Su, G. Coates, R.E. Routh, KJ McCarthy and H. Battarbee (2002) Troglitazone induces a cellular acidosis by inhibiting acid extrusion in cultured rat mesangial cells. Am J Physiol Regul Integr Comp Physiol 282: R1600-1607.
30. Bhati R, G Zibari, DJ Wassenhove-McCarthy, M Mancini, and KJ McCarthy  (2002).  Differential distribution of V3 and V5 integrins in vascular smooth muscle cells in regions of neointimal hyperplasia within stenosed vascular access grafts.  In “Vascular Access for Hemodialysis VIII”.  M. Henry and D. Campbell eds. ACCESS Medical Press, Arlington Heights, Illinois
31. Karim A, KJ McCarthy, A Jawahar, D Smith, B Wills, and Anil Nanda (2005) Differential cyclooxygenase-2 enzyme expression in radiosensitive versus radioresistant glioblastoma multiforme cell lines.  Anticancer Res 25: 675-680.
32. Karim, A., Fowler, M., Jones L. Patwardhan, R., Vaneemreddy P., McCarthy KJ, and Nanda A. (2005).  Cycloxygenase-2 expression in brain metastasis.  Anticancer Research  25: 2969-71.
33. Lauer, M, Scruggs, BS, Chen, Shoujun, Wassenhove-McCarthy, DJ, and KJ McCarthy (2007).  Tissue distribution of Leprecan in Developing and Adult Kidney.  Kidney International 72(1):82-91.
34. Wijnhoven TJM, JFM Lensen, ALWMM Rops, KJ McCarthy, J van der Vlag, JHM Berden, LPWJ van den Heuvel, and TH van Kuppevelt (2007). Glycosaminoglycan-based drugs as therapeutics for the treatment of proteinuria.  Current Opinion in Molecular Therapeutics 9: 364-377.
35. McCarthy KJ (2008) Basement Membranes: From the Matrisome to Beyond  Microscopy Research and Technique 71 (5): 335-338.
36. Chen, S, Y Yamaguchi, A Woods, L Holzman, DJ Wassenhove-McCarthy, T Van Kuppelvelt, G Jenniskens, T Winjhoven and McCarthy KJ,  (2008)  Loss of heparan sulfate glycosaminoglycan assembly in glomerular podocytes does not lead to rapidly developing proteinuria.  Kidney International. Kidney International 74 (3): 289-299. *Editorial Commentary for the article appears in same issue
37. Chen, S, Wassenhove-McCarthy, A Woods, L Holzman, Y Yamaguchi, T van Kuppevelt, and KJ McCarthy. (2010)  Cell surface heparan sulfate glycosaminoglycans are important in mediating cell-matrix adhesion in podocytes. Kidney International 78: 1088-1099.
38. S.M. Pyott, U. Schwarze, HE Christiansen, M Pepin, D Leistritz, R Dineen, K Ward, B Burton, B Engle, K Kim, M Sussman, R Steiner, KJ McCarthy, MA Weis, D Eyre, and PH Byers. Mutations in PPIB (cyclophilin B) delay type I procollagen chain association and result in perinatal lethal to moderate osteogenesis imperfecta phenotypes (2011). Human Molecular Genetics doi 10.1093 /hmgddr037.
39. KJ McCarthy and DJ Wassenhove-McCarthy. (2012) The glomerular basement membrane as a model system to study the bioactivity of heparan sulfate glycosaminoglycans. Microscopy and Microanalysis 18:3-21.
40. Sugar T, DJ Wassenhove-McCarthy, JD Esko, T van Kuppevelt, L Holzman, and KJ McCarthy (2014). Podocyte-specific deletion of NDST1, a key enzyme in the sulfation of heparan sulfate glycosaminoglycans, leads to abnormalities in podocyte organization in vivo.  Kidney International 85: 307-318
41. Sugar T, DJ Wassenhove-McCarthy, J. Green, AW Orr, T van Kuppevelt, and KJ McCarthy. N-sulfation of heparan sulfate glycosaminoglycans is a key, critical component in podocyte cell-matrix interactions. American Journal of Physiology-Renal Physiology, 310: F1123-F1135. *Editorial Focus for the article appears in American Journal of Physiology-Renal Physiology 311: F310-F311.
42. Jackson, KL, Lin, W, M Panchatcharam, , S Miriyala, KJ McCarthy, R Klein (2017) p62 pathology model in the rat substantia nigra with filamentous inclusions and progressive neurodegeneration.  In Press, PLOS one.
43. Chandra, M., D Escalante-Alcalde, MS Bhuiyan, AW Orr, C Kevil, AJ Morris, H Nam, P Dominic, KJ McCarthy, S Miriyala, M. Panchatcharam (2018).  Cardiac-specific inactivation of LPP3 in mice leads to myocardial dysfunction and heart failure.  Redox Biology 14: 261-271.

McCarthy Laboratory Personnel

Kevin J. McCarthy Ph.D., Professor and Chairman, Cellular Biology and Anatomy

Deborah Wassenhove-McCarthy B.S., Research Associate, Department of Pathology and Translational Pathobiology

Available Positions

The McCarthy Laboratory has an opening for a Full-Time Research Associate and an opening for a Part-Time Research Associate.  Please link to our job openings for further information.