Lack of Collagen XVIII Long Isoforms Affects Kidney Podocytes, whereas the Short Form Is Needed in the Proximal Tubular Basement Membrane

Kinnunen, Aino; Sormunen, Raija; Elamaa, Harri; Seppinen, Lotta; Miller, R. Tyler; Ninomiya, Yoshifumi; Janmey, Paul A.; Pihlajaniemi, Taina

doi:10.1074/jbc.m110.166132

Cited by 43 publications

(46 citation statements)

References 53 publications

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“…Kinnunen et al showed that although it is not noticeable in normal condition, the tubular BM of collagen XVIII deficient mice shows some structural abnormalities [16] which might result in an altered response after I/R and affect leukocyte influx and the degree of damage. However, that needs further research to be confirmed.…”

Section: Discussionmentioning

confidence: 99%

Basement Membrane Zone Collagens XV and XVIII/Proteoglycans Mediate Leukocyte Influx in Renal Ischemia/Reperfusion

et al. 2014

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Collagen type XV and XVIII are proteoglycans found in the basement membrane zones of endothelial and epithelial cells, and known for their cryptic anti-angiogenic domains named restin and endostatin, respectively. Mutations or deletions of these collagens are associated with eye, muscle and microvessel phenotypes. We now describe a novel role for these collagens, namely a supportive role in leukocyte recruitment. We subjected mice deficient in collagen XV or collagen XVIII, and their compound mutant, as well as the wild-type control mice to bilateral renal ischemia/reperfusion, and evaluated renal function, tubular injury, and neutrophil and macrophage influx at different time points after ischemia/reperfusion. Five days after ischemia/reperfusion, the collagen XV, collagen XVIII and the compound mutant mice showed diminished serum urea levels compared to wild-type mice (all p<0.05). Histology showed reduced tubular damage, and decreased inflammatory cell influx in all mutant mice, which were more pronounced in the compound mutant despite increased expression of MCP-1 and TNF-α in double mutant mice compared to wildtype mice. Both type XV and type XVIII collagen bear glycosaminoglycan side chains and an in vitro approach with recombinant collagen XVIII fragments with variable glycanation indicated a role for these side chains in leukocyte migration. Thus, basement membrane zone collagen/proteoglycan hybrids facilitate leukocyte influx and tubular damage after renal ischemia/reperfusion and might be potential intervention targets for the reduction of inflammation in this condition.

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Section: Discussionmentioning

confidence: 99%

Basement Membrane Zone Collagens XV and XVIII/Proteoglycans Mediate Leukocyte Influx in Renal Ischemia/Reperfusion

et al. 2014

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“…Thus, although additional studies are required to establish whether the COL18A1 c.331G > A variant itself (or an allele in linkage disequilibrium) is responsible for the triglyceride-lowering effect, from the data presented herein it seems conceivable that COL18A1 variants having a major deleterious impact on collagen XVIII's DUF/Fz sequences could cause atherogenic dyslipidemia and fatty liver, secondary to impaired adipogenesis. Furthermore, we note that factors regulating collagen XVIII expression may contribute to kidney health in later life by affecting the BM of proximal tubules (short isoform) and of glomerular podocyte foot processes (medium/long isoforms) (19). It may also be clinically relevant that short collagen XVIII is expressed widely in the BM of the retina, and that the retinal vessels of P1-, but not P2-mice develop the same vessel outgrowth abnormality seen in Col18a1 −/− mice (50).…”

Section: Discussionmentioning

confidence: 99%

Specific collagen XVIII isoforms promote adipose tissue accrual via mechanisms determining adipocyte number and affect fat deposition

Aikio

Elamaa

Vicente

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Collagen XVIII is an evolutionary conserved ubiquitously expressed basement membrane proteoglycan produced in three isoforms via two promoters (P). Here, we assess the function of the N-terminal, domain of unknown function/frizzled-like sequences unique to medium/long collagen XVIII by creating P-specific null mice. P2-null mice, which only produce short collagen XVIII, developed reduced bulk-adiposity, hepatic steatosis, and hypertriglyceridemia. These abnormalities did not develop in P1-null mice, which produce medium/long collagen XVIII. White adipose tissue samples from P2-null mice contain larger reserves of a cell population enriched in early adipocyte progenitors; however, their embryonic fibroblasts had ∼50% lower adipocyte differentiation potential. Differentiating 3T3-L1 fibroblasts into mature adipocytes produced striking increases in P2 gene-products and dramatic falls in P1-transcribed mRNA, whereas Wnt3a-induced dedifferentiation of mature adipocytes produced reciprocal changes in P1 and P2 transcript levels. P2-derived gene-products containing frizzledlike sequences bound the potent adipogenic inhibitor, Wnt10b, in vitro. Previously, we have shown that these same sequences bind Wnt3a, inhibiting Wnt3a-mediated signaling. P2-transcript levels in visceral fat were positively correlated with serum free fatty acid levels, suggesting that collagen α1 (XVIII) expression contributes to regulation of adipose tissue metabolism in visceral obesity. Medium/long collagen XVIII is deposited in the Space of Disse, and interaction between hepatic apolipoprotein E and this proteoglycan is lost in P2-null mice. These results describe a previously unidentified extracellular matrix-directed mechanism contributing to the control of the multistep adipogenic program that determines the number of precursors committing to adipocyte differentiation, the maintenance of the differentiated state, and the physiological consequences of its impairment on ectopic fat deposition.

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“…More recently, we measured the E of mouse and rat glomeruli using atomic force microscopy, micro-indentation, and microfluidics, and obtained values of 2–3 kPa [14–16]. Although these studies measured isolated glomeruli that were not perfused, they detected physiologically meaningful alterations in glomerular elasticity because they demonstrated a reduced E with actin depolymerization (cytochalasin-D and latrunculin) and inhibition of non-muscle myosin II activity (blebbistatin) as well as in two disease states, Tg26 mice, a model of HIV nephropathy, and Col4a3 -/- mice, a model of Alport syndrome [15,16]. The reduced glomerular E in these models was surprising because the conventional view is that following injury, fibrosis develops progressively leading to a stiff, nonfunctional tissue.…”

Section: Introductionmentioning

confidence: 99%

Biochemical and Cellular Determinants of Renal Glomerular Elasticity

et al. 2016

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The elastic properties of renal glomeruli and their capillaries permit them to maintain structural integrity in the presence of variable hemodynamic forces. Measured by micro-indentation, glomeruli have an elastic modulus (E, Young’s modulus) of 2.1 kPa, and estimates from glomerular perfusion studies suggest that the E of glomeruli is between 2 and 4 kPa. F-actin depolymerization by latrunculin, inhibition of acto-myosin contractility by blebbistatin, reduction in ATP synthesis, and reduction of the affinity of adhesion proteins by EDTA reduced the glomerular E to 1.26, 1.7, 1.5, and 1.43 kPa, respectively. Actin filament stabilization with jasplakinolide and increasing integrin affinity with Mg2+ increased E to 2.65 and 2.87 kPa, respectively. Alterations in glomerular E are reflected in commensurate changes in F/G actin ratios. Disruption of vimentin intermediate filaments by withaferin A reduced E to 0.92 kPa. The E of decellularized glomeruli was 0.74 kPa, indicating that cellular components of glomeruli have dominant effects on their elasticity. The E of glomerular basement membranes measured by magnetic bead displacement was 2.4 kPa. Podocytes and mesangial cells grown on substrates with E values between 3 and 5 kPa had actin fibers and focal adhesions resembling those of podocytes in vivo. Renal ischemia and ischemia-reperfusion reduced the E of glomeruli to 1.58 kPa. These results show that the E of glomeruli is between 2 and 4 kPa. E of the GBM, 2.4 kPa, is consistent with this value, and is supported by the behavior of podocytes and mesangial cells grown on variable stiffness matrices. The podocyte cytoskeleton contributes the major component to the overall E of glomeruli, and a normal E requires ATP synthesis. The reduction in glomerular E following ischemia and in other diseases indicates that reduced glomerular E is a common feature of many forms of glomerular injury and indicative of an abnormal podocyte cytoskeleton.

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Lack of Collagen XVIII Long Isoforms Affects Kidney Podocytes, whereas the Short Form Is Needed in the Proximal Tubular Basement Membrane

Cited by 43 publications

References 53 publications

Basement Membrane Zone Collagens XV and XVIII/Proteoglycans Mediate Leukocyte Influx in Renal Ischemia/Reperfusion

Basement Membrane Zone Collagens XV and XVIII/Proteoglycans Mediate Leukocyte Influx in Renal Ischemia/Reperfusion

Specific collagen XVIII isoforms promote adipose tissue accrual via mechanisms determining adipocyte number and affect fat deposition

Biochemical and Cellular Determinants of Renal Glomerular Elasticity

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