Biologic modulation in renal regeneration

ABSTRACT

Introduction: Chronic kidney disease (CKD) is recognized as a health care problem of increasing importance. Following the discovery of renal progenitors, the investigation of new therapeutic approaches to promote the kidney regenerative capacity has received increasing research attention.

Areas covered: The authors discuss the current knowledge of glomerular regeneration by renal progenitors and the modulation of their behavior through chemical and biological agents. The regenerative capacity of renal progenitors after injury must be regulated in order to prevent an inefficient or excessive response that could lead to a failed attempt to replace lost podocytes. In addition, they discuss the most relevant pathways involved in tubular repair and how these could be modulated in order to obtain renal regeneration rather than progression of a fibrotic maladaptive response.

Expert opinion: Modulation of the endogenous renal regenerative capacity is a new approach in the treatment of kidney diseases. Research efforts that concentrate on the potential regenerative capacity of the kidney can be advantageous when the experimental results are translated into clinical practice and may open the way to new therapeutic strategies for CKD.

KEYWORDS:

• Chronic renal failure
• AKI
• progression
• CKD
• tubule
• glomerulus

Article highlights

• Glomerular regeneration is mainly driven by Renal Progenitors Cells (RPCs).

• Cells of renine lineage (CoRL) were described as a putative source of parietal epithelial cells that, in turn, regenerate podocytes.

• Targeting of several potential pathways may accelerate the regenerative response of RPCs through the modulation of their differentiation and proliferation.

• Several drugs or biological mediators may potentially modulate RPC capacity to proliferate and differentiate into podocytes and may thus be used to enhance glomerular regeneration.

• The existence of a hypothetical population of tubular progenitors has been described in human adult kidney. Further studies are needed to enhance our knowledge of tubular regenerative capacity and to establish the role of putative tubular progenitors in response to injury.

• Targeting of several potential pathways may accelerate the regenerative response of tubular epithelial cells through maladaptive response inhibition.

This box summarizes key points contained in the article.

Explanatory boxKidney architecture

• The nephron is the basic structural and functional unit of the kidney; it is considerably similar across phyletic groups and it is generated in a highly conserved manner. In mammals, the number of nephrons is roughly proportional to the body mass.

• Each nephron consists of a glomerulus, the filtering unit, which is connected through a neck to a tubule, specialized for reabsorption and secretion.

• The glomerulus is composed of a Bowman’s capsule and a network (as a tuft) of capillaries.

• The Bowman’s capsule is composed of parietal epithelial cells and renal progenitor cells.

• The tubule is divided into a proximal tubule, Henle’s loop (thin descending limb, thin ascending limb, and thick ascending limb), and a distal tubule that connects to an excretion unit.

Critical cells of the nephron for the renal regeneration

• The podocytes represent one of the three components of the glomerular filtration barrier together with the fenestrated endothelial cell and the glomerular basement membrane (GBM). These cells have limited capacity to divide and they cannot restore glomerular architecture through cell division. For this reason, the replacement of these cells by an intrarenal glomerular progenitor is critical.

• Tubular epithelial cells play a central role in renal physiology and are the cell types most sensitive to ischemic and nephrotoxic injury. The high regenerative capacity of these cells after kidney injury is in the last decade questioned because epidemiological studies document that even mild AKI episodes imply a substantial risk of CKD that progresses toward ESRD because of the occurrence of maladaptive repair processes. For this reason, a better knowledge of several potential pathways that may accelerate the regenerative response of tubular epithelial cells through maladaptive response inhibition is mandatory.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This study was supported by the European Research Council under the Consolidator Grant RENOIR (ERC-2014-CoG, grant 648274).