Nephrogenesis is induced by partial nephrectomy in the elasmobranch Leucoraja erinacea

The mammalian kidney responds to partial nephrectomy with glomerular and tubular hypertrophy, but without renal regeneration. In contrast, renal regeneration in lower vertebrates is known to occur. Understanding the underlying mechanisms of renal regeneration is highly important; however, a serviceable animal model has not been developed. A neonephrogenic zone has been identified in the European lesser spotted dogfish, Scyliorhinus caniculus (Hentschel H. Am J Anat 190: 309-333, 1991), as well as in the spiny dogfish Squalus acanthias and the little skate, Leucoraja erinacea. The zone features the production of new nephrons complete with a countercurrent system. To analyze this nephrogenic region of elasmobranch fish further, a renal reduction model was established. The neonephrogenic zone in the adult kidney of the little skate resembles the embryonic metanephric kidney and contains stem cell-like mesenchymal cells, tips of the branching collecting duct system, and outgrowth of the arterial system. Four stages of nephron development were analyzed by serial sections and defined: stage I, aggregated mesenchymal cells; stage II, S-shaped body-like structure with high-prismatic epithelial cells; stage III, segmental nephron segregation; stage IV, functioning nephron. The stages were analyzed after partial nephrectomy. In addition, cell proliferation was assessed by incorporation of bromo-deoxyuridine (BrdU). New nephrons developed in animals undergoing partial nephrectomy. Growth was greatly stimulated in the nephrogenic zone, both in the remnant tissue and in the contralateral kidney within 10 wk. Mesenchymal cell aggregates increased significantly per renal cross-section compared with controls (stage I, 0.64 +/- 0.28 versus 0.27 +/- 0.25; P < 0.005; n = 10 animals per group). The same was the case for S-shaped body-like cysts (stage II, 0.24 +/- 0.19 versus 0.08 +/- 0.09; P < 0.02). Cellular proliferation in the neonephrogenic zone of the contralateral kidney was also greatly enhanced (14.42 +/- 3.26 versus 2.64 +/- 1.08 BrdU-positive cells per cross-section, P < 0.001). It is concluded that the skate possesses a nephrogenic zone containing stem cell-like mesenchymal cells during its entire life. Partial nephrectomy induces renal growth by accelerating nephrogenesis. This unique model may facilitate understanding renal regeneration

Podocyte injury underlies the progression of focal segmental glomerulosclerosis in the fa/fa Zucker rat

Podocyte injury underlies the progression of focal segmental glomerulosclerosis in the fa/faZucker rat.BackgroundThe progression of diabetic nephropathy to chronic renal failure is based on the progressive loss of viable nephrons. The manner in which nephrons degenerate in diabetic nephropathy and whether the injury could be transferred from nephron to nephron are insufficiently understood. We studied nephron degeneration in the fa/fa Zucker rat, which is considered to be a model for non-insulin-dependent diabetes mellitus.MethodsKidneys of fa/fa rats with an established decline of renal function and of fa/+ controls were structurally analyzed by advanced morphological techniques, including serial sectioning, high-resolution light microscopy, transmission electron microscopy, cytochemistry, and immunohistochemistry. In addition, tracer studies with ferritin were performed.ResultsThe degenerative process started in the glomerulus with damage to podocytes, including foot process effacement, pseudocyst formation, and cytoplasmic accumulation of lysosomal granules and lipid droplets. The degeneration of the nephron followed the tuft adhesion-mediated pathway with misdirected filtration from capillaries included in the adhesion toward the interstitium. This was followed by the formation of paraglomerular spaces that extended around the entire glomerulus, as well as via the glomerulotubular junction, to the corresponding tubulointerstitium. This mechanism appeared to play a major role in the progression of the segmental glomerular injury to global sclerosis as well as to the degeneration of the corresponding tubule.ConclusionsThe way a nephron undergoes degeneration in this process assures that the destructive effects remain confined to the initially affected nephron. No evidence for a transfer of the disease from nephron to nephron at the level of the tubulointerstitium was found. Thus, each nephron entering this pathway to degeneration appears to start separately with the same initial injuries at the glomerulus

ELMO1 protects renal structure and ultrafiltration in kidney development and under diabetic conditions

Engulfment and cell motility 1 (ELMO1) functions as a guanine exchange factor for Rac1 and was recently found to protect endothelial cells from apoptosis. Genome wide association studies suggest that polymorphisms within human elmo1 act as a potential contributing factor for the development of diabetic nephropathy. Yet, the function of ELMO1 with respect to the glomerulus and how this protein contributes to renal pathology was unknown. Thus, this study aimed to identify the role played by ELMO1 in renal development in zebrafish, under hyperglycaemic conditions, and in diabetic nephropathy patients. In zebrafish, hyperglycaemia did not alter renal ELMO1 expression. However, hyperglycaemia leads to pathophysiological and functional alterations within the pronephros, which could be rescued via ELMO1 overexpression. Zebrafish ELMO1 crispants exhibited a renal pathophysiology due to increased apoptosis which could be rescued by the inhibition of apoptosis. In human samples, immunohistochemical staining of ELMO1 in nondiabetic, diabetic and polycystic kidneys localized ELMO1 in glomerular podocytes and in the tubules. However, ELMO1 was not specifically or distinctly regulated under either one of the disease conditions. Collectively, these results highlight ELMO1 as an important factor for glomerular protection and renal cell survival via decreasing apoptosis, especially under diabetic conditions