Glomerular hypertrophy precedes albuminuria and segmental loss of podoplanin in podocytes in Munich-Wistar-Frömter rats

Abstract

Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage renal disease. Albuminuria is a risk factor for FSGS and is influenced by environmental, genetic, and sex-specific factors. Podocytes play a central role in the development of albuminuria, but the precise relationship between early glomerular and podocyte-associated damage and albuminuria is unclear. Furthermore, experimental findings demonstrate a sex difference in development of albuminuria and FSGS. We investigated the early glomerular changes in male Munich-Wistar-Frömter (MWF) rats, which spontaneously develop albuminuria, and male albuminuria-resistant spontaneously hypertensive rats (SHR). In addition, since female MWF rats are protected from overt proteinuria and progressive renal disease, we compared the phenotypic changes in podocytes during early development of albuminuria in male and female MWF rats. In male MWF rats, glomerular hypertrophy preceded the onset of albuminuria and was greater than in male SHR. Albuminuria developed starting at 6 wk of age and coincided with focal and segmental loss of podoplanin, increased expression of desmin, entrapment of albumin in affected podocytes, and focal and segmental foot process effacement at the ultrastructural level. Other podocyte-associated molecules, such as nephrin and zonula occludens 1, were unaffected. Early glomerular hypertrophy and podocyte damage did not differ between male and female MWF rats. Our data show for the first time that albuminuria in male and female MWF rats is preceded by glomerular hypertrophy and accompanied by focal and segmental loss of podoplanin when FSGS was not yet present.

Persistent antihypertensive effect of aliskiren is accompanied by reduced proteinuria and normalization of glomerular area in Ren-2 transgenic rats

“…In contrast, Whaley-Connell et al (38) reported similar effects of irbesartan and aliskiren on podocyte injury in young Ren-2 rats, while irbesartan had a greater BP-lowering effect. Our findings are in agreement with the findings of Ijpellar et al (13), who found that glomerular hypertrophy precedes albuminuria and proteinuria in Munich-Wistar-Frömter (MWF) rats. It appears that the expansion of glomerular tuft requires adaptation of podocytes to cover a larger area of glomerular capillary wall (16), and this situation requires reorganization of the podocyte cytoskeleton.…”

Podocyte Number in Children and Adults

“…Glomerular hypertrophy plays pivotal roles in the development of FSGS 2,18,19 and the progression of diabetic nephropathy, [35][36][37][38] two of the most common causes of CKD. According to the hyperfiltration theory, 25 an imbalance between glomerular mass and physiologic requirements drives glomerular hypertrophy as an appropriate compensatory response to sustain renal function.…”

“…Glomerular size increases with normal body growth as well before and during multiple renal pathologies, including both diabetic nephropathy [13][14][15][16][17] and FSGS. [18][19][20][21][22][23][24] It has been suggested that an increase in glomerular size (also known as glomerular hypertrophy) is usually a compensatory mechanism that serves to match physiologic demands and sustain renal function. 25 Over the last decade, our group has described multiple factors associated with compensatory glomerular hypertrophy in humans without overt renal disease, including older age, low nephron number (N glom ), obesity, hypertension, and African-American race.…”

Mapping genetic determinants of kidney damage in rat models

“…Hence, studies in the FHH, 90,93,95,97 MWF [141][142][143] and SS 53,54 rat models highlighted the role of major susceptibility loci that in concert and genetic interaction with multiple other loci influence renal disease susceptibility (Table 5). Moreover, these models allow the combination of genetic analyses with unlimited gene expression studies, 65,70,150 including timed renal and compartment-specific expression analysis during the onset of renal disease phenotypes such as albuminuria, 143,204 while these experimental algorithms are difficult or impossible to pursue in humans due to the limited access to renal tissue. The comprehensive exploitation of the genotype-renal phenotype associations that are inherited in this panel of rat strains is therefore suitable for making a significant contribution to the development of an integrated approach to the systems genetics of CKD.…”