Mesangial Cells Regulate the Glomerular Filtration Rate: A Multiphoton Microscopy Study

Abstract

The intra‐glomerular mesangial cells fill the space between the glomerular capillaries and may support the structural integrity of the glomerulus. Data from cultured mesangial cells suggest a contractile cell phenotype. However, the in vivo relevance of mesangial cells for the function of the glomerular filtration barrier and the regulation of glomerular filtration remains unclear.Here we hypothesized that contractile mesangial cells actively regulate the single nephron glomerular filtration rate (snGFR) and that mesangial cells support the integrity of the glomerular filtration barrier. To test this hypothesis, we assessed the function of mesangial cells in the life animal by intravital multiphoton microscopy. Mesangial cells were depleted in Munich Wistar Froemter rats using the Thy1.1 antibody model. Administration of the Thy1.1 antibody (1 mg/kg BW) caused the loss of approximately 80% of mesangial cells. Immune‐staining of kidneys for Thy1.1 showed an exclusive binding of the antibody to mesangial cells. To assess if mesangial cells contribute to the regulation of snGFR by vasoconstrictor agents, angiotensin II (12.8 ng/kg/min) was infused during intravital imaging. In response to angiotensin II, the systolic arterial blood pressure rose from 100.5 to 125.1 mm Hg mm Hg in Thy1.1‐treated rats (n=17; p<.0001), and, similarly, from 98.8 mm Hg to 125.2 mm Hg in controls (n=19; p<.0001). SnGFR, as determined by flow measurements in the proximal tubule after bolus injections of Lucifer Yellow, decreased after angiotensin II infusion by 35±12% in controls (n=5; p=.004), whereas it remained unchanged in Thy1.1‐treated rats (−12±10%, n=5). In control rats, changes in snGFR after angiotensin II infusion were accompanied by a marked rotating movement of the capillary loops within Bowman’s space. This phenomenon was absent in Thy1.1‐treated rats. In addition, glomerular capillaries at baseline were dilated, and blood flow velocity was reduced in Thy1.1‐treated rats compared with controls, whereas the calculated capillary flow was similar in both groups (5.8±.6 nl/min in controls vs. 4.9±.5 nl/min in Thy1.1‐treated rats; n=6; n.s.). Glomerular capillary flow declined in response to angiotensin II in controls but it remained unchanged in Thy1.1‐treated rats (2.7±.2 nl/min vs. 3.7±.4 nl/min, respectively).Next, to determine the relevance of mesangial cells for the integrity of the glomerular barrier function, we measured the sieving coefficient for albumin (GSC). Albumin GSC was low in control rats averaging 0.00059±.00006. After angiotensin II infusion, the GSC for albumin increased to 0.00112±.00015 in control rats (n=8; p<.0001). In contrast, in Thy1.1‐treated rats, baseline albumin GSC was elevated (0.0033±.00080; n=7; p<.0001) and did not change in response to angiotensin II (0.0047±.001; n.s.).In summary, the depletion of mesangial cells by Thy1.1 antibody application abolished the regulation of the snGFR by angiotensin II and markedly increased the permeability of the filtration barrier for plasma proteins. Or data suggest that mesangial cells contribute to the regulation of the snGFR in vivo. Furthermore, mesangial cells are crucially involved in the maintenance of the integrity of the glomerular filtration barrier.Support or Funding InformationSFB 1350/B2