New Aspects of Kidney Fibrosis-From Mechanisms of Injury to Modulation of Disease

Abstract

Organ fibrogenesis is characterized by a common pathophysiological final pathway independent of the underlying progressive disease of the respective organ. This makes it particularly suitable as a therapeutic target. The Transregional Collaborative Research Center "Organ Fibrosis: From Mechanisms of Injury to Modulation of Disease" (referred to as SFB/TRR57) was hosted from 2009 to 2021 by the Medical Faculties of RWTH Aachen University and the University of Bonn. This consortium had the ultimate goal of discovering new common but also different fibrosis pathways in the liver and kidneys. It finally successfully identified new mechanisms and established novel therapeutic approaches to interfere with hepatic and renal fibrosis. This review covers the consortium's key kidney-related findings, where three overarching questions were addressed: (i) What are new relevant mechanisms and signaling pathways triggering renal fibrosis? (ii) What are new immunological mechanisms, cells and molecules that contribute to renal fibrosis?, and finally (iii) How can renal fibrosis be modulated?

Keywords: crystals; deep learning; fibrosis imaging; inflammasome; lupus erythematodes; myofibroblast; parietal epithelial cell; renal fibrosis.

Figure 1

The main cellular source of kidney myofibroblasts following kidney injury and fibrosis progression are resident renal fibroblasts and pericytes.

Figure 2

Identification of different kidney myofibroblast subtypes in renal fibrosis. In kidney fibrosis two different types of myofibroblasts could be discriminated: PDGFRβ⁺/CD45⁻ myofibroblasts and PDGFRβ⁺/CD45⁺ myofibroblasts-like cells. PDGFRβ⁺/CD45⁻ fibroblasts originate from pericytes and fibroblasts but not from proximal tubule epithelium and secrete extracellular matrix proteins. Circulating cells of the hematopoietic lineage differentiate in PDGFRβ⁺/CD45⁺ myofibroblasts-like cells. These myofibroblasts-like cells secrete extracellular matrix, pro-inflammatory, profibrotic chemokines and interact via receptor-ligand-binding with PDGFRβ⁺/CD45⁻ myofibroblasts.

Figure 3

Simplified scheme to illustrate renal inflammasome activation by two disease entities, finally leading to renal fibrosis. SLE, systemic lupus erythematosus; MDSCs, myeloid-derived suppressor cells. Modified based on (25).

Figure 4

Three known gene defects in hepatocytes cause oxalate accumulation in primary Hyperoxaluria I-III. Ca-Oxalate crystals precipitate in the kidney where water gets reabsorbed and the solubility coefficient of this salt is exceeded. The crystals activate the inflammasome in renal macrophages and dendritic cells, which stimulate interstitial fibroblasts to deposits collagen, resulting in kidney fibrosis.

Figure 5

The figure summarizes some central aspects of the repair and modulation of renal fibrosis that have been successfully investigated in our consortium. PODs, podocytes; fPECs, flat parietal cells; PTLC, proximal tubular epithelial-like cell, PDGFs, platelet-derived growth factors; MIF, macrophage migration inhibitory factor.

Figure 6

Pathogenesis of sclerotic lesions in FSGS. (A) Normal glomerulus. gray, podocytes; white, parietal epithelial cells. (B) Podocyte injury or loss triggers focal PEC activation (red), PECs form an adhesion to the capillary tuft (arrow). (C) PECs take over parts of the capillary segment, capillaries are lost. (D) Advanced stage. Figure taken from (56) with modifications.

Figure 7

Imaging kidney fibrosis. (A) 2D and 3D images reconstructed from contrast-enhanced micro-CT imaging show progressive vessel rarefaction in mice with I/R-induced kidney fibrosis. Scale bar: 200 μm. (B) Molecular imaging of collagen deposition in the kidneys of mice with I/R-induced fibrosis, employing CNA35 and CT-FMT. (C) Validation of CNA35 binding to perivascular collagen fibers in mice with I/R-induced kidney fibrosis. Perfused blood vessels are stained with lectin. (D) ESMA-enhanced molecular MR imaging of elastin deposition in the kidneys of mice with adenine diet-induced fibrosis. (E–G) In the adenine reversal model (14 days on adenine diet, then 14 days recovery), ESMA-based molecular MRI can detect residual fibrosis that is not detected by routine kidney function assessment, i.e. analysis of creatinine clearance. Scale bar in (E): 50 μm. Images reproduced, with permission, from (–59). For assessing statistical significance, as shown in (F) and (G), one-way analysis of variance (ANOVA) followed by Bonferroni correction was used. Statistical significance was defined as *p < 0.05; **p < 0.01; ***p < 0.001.