Biomedical subjects

Peter Kossmehl

Publications and source records attributed to Peter Kossmehl.

At least 19 recordsLinked to original sources

PubMed2007

Rat chromosome 19 transfer from SHR ameliorates hypertension, salt-sensitivity, cardiovascular and renal organ damage in salt-sensitive Dahl rats.

OBJECTIVES: Unlike Dahl salt-sensitive (SS) rats, some strains of spontaneously hypertensive (SHR) rats develop only minor organ damage even when exposed to high-salt diet. In previous linkage studies, we identified quantitative trait loci on rat chromosome 19 (RNO19) linked to the SHR allele suggesting a protective effect against salt-induced hypertensive organ damage in SS. METHODS: To test the relevance of this finding, we generated and characterized a consomic strain SS-19SHR in which RNO19 from SHR was introgressed into the susceptible background of SS. We compared the effects of low-salt (0.2% NaCl) and high-salt (4% NaCl) diet exposure for 8 weeks on the development of hypertension and target organ damage in male consomic and SS animals (n=14-20, each). RESULTS: Systolic blood pressure, relative left ventricular weight and urinary protein excretion were significantly lower in SS-19SHR compared to SS under both low-salt and high-salt diet (P < 0.05, respectively). Left ventricular atrial natriuretic peptide mRNA expression showed a more pronounced 4.5-fold increase in SS compared to SS-19 (two-fold) after high-salt (P < 0.05). In comparison to low diet, high-salt exposure induced a significant increase in vascular aortic hypertrophy index, left ventricular interstitial fibrosis (+210%) and perivascular fibrosis (+195%) in SS but not in consomic SS-19SHR (P < 0.05, respectively). CONCLUSIONS: These results demonstrate a strong protective effect of RNO19 from SHR on the development of hypertension, salt-sensitivity, cardiovascular and renal organ damage in SS. In particular, we demonstrate a genetic effect protecting against the development of cardiac fibrosis in salt-sensitive hypertension.

Animals↗

PubMed2006

Development of overt proteinuria in the Munich Wistar Frömter rat is suppressed by replacement of chromosome 6 in a consomic rat strain.

In a cross between the Munich Wistar Frömter (MWF) rat and spontaneously hypertensive rats (SHR), a major quantitative trait locus (QTL) was identified on rat chromosome 6 (RNO6) that demonstrated the strongest linkage to albuminuria among several QTL identified. The QTL represented the only locus that is linked to both early-onset albuminuria and increased renal interstitial fibrosis in adult animals. A consomic MWF-6(SHR) strain in which chromosome 6 from SHR was introgressed into the MWF background therefore was generated to test the relevance of this QTL. Phenotype analysis at 8 wk of age revealed that early onset of albuminuria in MWF with a 55-fold elevation of urinary albumin excretion compared with SHR (P < 0.0001) was completely abolished in MWF-6(SHR). Time-course analysis until week 24 demonstrated only a moderate increase of urinary albumin excretion in MWF-6(SHR), whereas MWF reached levels in the nephrotic range (16.6 +/- 3.5 versus 162.6 +/- 16.0 mg/24 h; P < 0.0001). At this age, analysis of glomerulosclerosis, tubulointerstitial damage, renal interstitial fibrosis, and renal collagen III mRNA expression revealed a significant improvement of all parameters in MWF-6(SHR) compared with MWF (P < 0.05). At 32 wk, MWF but not MWF-6(SHR) demonstrated overt proteinuria (354.6 +/- 37.6 versus 48.8 +/- 13.2; P < 0.0001), whereas serum urea, cholesterol, and triglyceride concentrations were lower and creatinine clearance was higher in MWF-6(SHR) compared with MWF (P < 0.05). Therefore, although albuminuria in MWF is determined by a complex interplay of several QTL, our data demonstrate that genetic exchange of one locus on RNO6 leads to marked suppression of early-onset albuminuria and renal damage in MWF.

Albuminuria↗

PubMed2006

Simulated weightlessness changes the cytoskeleton and extracellular matrix proteins in papillary thyroid carcinoma cells.

Studies of astronauts, experimental animals, and cells have shown that, after spaceflights, the function of the thyroid is altered by low-gravity conditions. The objective of this study was to investigate the cytoskeleton and extracellular matrix (ECM) protein synthesis of papillary thyroid cancer cells grown under zero g. We investigated alterations of ONCO-DG 1 cells exposed to simulated microgravity on a three-dimensional random-positioning machine (clinostat) for 30 min, 24 h, 48 h, 72 h, and 120 h (n=6, each group). ONCO-DG 1 cells grown under microgravity exhibited early alterations of the cytoskeleton and formed multicellular spheroids. The cytoskeleton was disintegrated, and nuclei showed morphological signs of apoptosis after 30 min. At this time, vimentin was increased. Vimentin and cytokeratin were highly disorganized, and microtubules (alpha-tubulin) did not display their typical radial array. After 48 h, the cytoskeletal changes were nearly reversed. The formation of multicellular spheroids continued. In parallel, the accumulation of ECM components, such as collagen types I and III, fibronectin, chondroitin sulfate, osteopontin, and CD44, increased. The levels of both transforming growth factor beta-1 (TGF-beta(1)) and TGF-beta receptor type II proteins were elevated from 24 h until 120 h clinorotation. Gene expression of TGF-beta(1) was clearly enhanced during culture under zero g. The amount of E-cadherin was enhanced time-dependently. We suggest that simulated weightlessness rapidly affects the cytoskeleton of papillary thyroid carcinoma cells and increases the amount of ECM proteins in a time-dependent manner.

Carcinoma, Papillary↗

PubMed2006

Successful microsurgical primary replantation of an amputated cheek.

Standard secondary reconstruction procedures are usually applied for the amputation of facial soft tissue, although these procedures lead to unsatisfactory results: in case of an avulsed cheek, a number of important vital cheek functions cannot be restored. More importantly, patients with artificial cheeks often face considerable psychological and social difficulties. Therefore, it appeared to be of interest to conserve soft tissue amputated from the face and to perform a replantation, despite the known problem that cheek veins cannot be re-anastomosed, especially in avulsion injuries. Here, we report a successful microsurgical cheek replantation in a 55-year-old female patient, who had lost cheek soft tissue together with parts of her mouth.

Amputation, Traumatic↗

PubMed2006

Genetic low nephron number hypertension is associated with dysregulation of the hepatic and renal insulin-like growth factor system during nephrogenesis.

OBJECTIVE: Low nephron number may represent a major determinant of human primary hypertension in adult life. This hypothesis is supported by a genetic rat model, namely the Munich-Wistar-Frömter (MWF) rat, which demonstrates an inherited deficit in nephron number and the development of spontaneous hypertension. Insulin-like growth factor (IGF) I and II exert endocrine and paracrine effects that are required for normal growth and nephron development. We tested the hypothesis that low nephron number is already present during fetal development, and the expression pattern of important molecules of the IGF system is altered in MWF rat during the critical period of kidney development. METHODS: We compared MWF and normal Wistar rats during nephrogenesis at day 19 of fetal development (E19) and adult rats at postnatal day 100 (D100). Histomorphometric analysis was performed by stereological methods. Quantitative messenger RNA and protein expression was determined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: At E19, glomerular density (-32%) and hepatic mRNA (-48%) and protein (-18%) expression of IGF-I were decreased (P < 0.05, respectively), whereas renal mRNA expression of IGF-II receptor (+52%) and IGF binding protein 3 (+113%) were increased in MWF compared with Wistar rats (P < 0.05, respectively). Systolic blood pressure, urinary albumin excretion, and mean glomerular area were significantly elevated in MWF compared with Wistar rats at D100 (P < 0.05, respectively). CONCLUSIONS: The fetal expression of IGF system molecules in the MWF rat model points towards a link between the decreased availability of active IGF-I and IGF-II and the fetal development of low nephron number, with manifestation of genetic hypertension in adult life.

Animals↗

PubMed2005

Intraluminal application of vascular endothelial growth factor enhances healing of microvascular anastomosis in a rat model.

BACKGROUND: Early reconstitution after injury to the endothelium is an important feature for reducing a number of vessel wall pathologies. We investigated the effect of vascular endothelial growth factor (VEGF) and its impact on the vascular remodeling process and reendothelialization after microsurgery. METHODS AND RESULTS: Microvascular anastomosis was performed in the rat femoral artery. One group was treated with intraluminal administration of VEGF and the other with vehicle. We investigated morphological, ultrastructural and immunohistochemical changes of the vascular wall and the reendothelialization process. After 10 days, reendothelialization was significantly faster in VEGF-treated rats. Transmission electron microscopy revealed a complete healing in contrast to vehicle-treated vessels. Moreover, extracellular matrix proteins, such as fibronectin, collagen types I, III and IV, were significantly increased. Furthermore, VEGF treatment significantly induced VEGF receptor 2, flk-1, osteopontin and TGF-beta(1) proteins. CONCLUSIONS: Our data clearly document for the first time that intraluminal treatment with VEGF is beneficial to the healing process in vascular microsurgery. Osteopontin and TGF-beta(1), both induced by VEGF, may play an important role in the vascular remodeling process. Our results provide clear evidence that VEGF application may represent a useful strategy in accelerating reendothelialization and improving vascular healing after microsurgery.

Administration, Topical↗

PubMed2005

Increase of fibronectin and osteopontin in porcine hearts following ischemia and reperfusion.

Following a severe ischemic injury or myocardial infarction, the extracellular matrix (ECM) of the heart is involved in pathophysiological conditions such as dilatation and cardiac dysfunction. Osteopontin (OPN) has been shown to interact with fibronectin suggesting its possible role in matrix organization, stability and wound healing. There is increased expression of OPN in several tissues in response to injury. Therefore, we tested the hypothesis that acute ischemia (2 h), followed by reperfusion (4 h) may induce early OPN and fibronectin in an isolated hemoperfused working porcine heart model. Twenty hearts were prepared and connected to a perfusion system. After 1 h of perfusion, these hearts were randomized to two groups: ten infarcted (MI, ramus circumflexus) and ten non-infarcted hearts (C). In addition, cardiac fibroblasts derived from infarcted, remote and control myocardium were investigated. In both groups, the heart rate, electrolytes, pH, blood gases, and lactate remained similar. The LVEDP and perfusion pressure of MI hearts increased significantly (P<0.05). The total fibronectin and OPN volume contents were clearly elevated in the infarct area. The matrix metalloproteinases (MMP-1 and MMP-8), fibronectin, OPN, TGF-beta1 proteins and the mRNAs for fibronectin, TGF-beta1, and OPN were significantly elevated in the infarct area as compared to the remote area and the non-infarcted hearts. Simultaneously, circulating carboxyterminal propeptide of type I procollagen (PICP) was released in the perfusion medium (threefold versus C). Fibroblast-like cells originating from the infarct area exhibited an enhanced OPN and fibronectin gene and protein expression compared to fibroblasts derived from control myocardium. Our data demonstrate the early appearance of the MMPs (increased collagen degrading enzymes) and PICP (a collagen synthesis marker) following ischemia and reperfusion. Moreover, OPN, fibronectin and TGF-beta1 protein and gene expression are elevated after ischemia and reperfusion in the ex vivo working hemoperfused porcine heart model.

Animals↗

PubMed2005

Surgical and medical management of rare echinococcosis of the extremities: pre- and post-operative long-term chemotherapy.

Skeletal hydatid disease is a rare parasitic infection caused by the tapeworm Echinococcus granulosus. We present the case of a 30-y-old patient with an echinococcosis of the right leg, who was treated with a preoperative albendazole chemotherapy (4 weeks), followed by radical surgical resection and postoperative albendazole treatment (1 y).

Adult↗

PubMed2004

Genetic linkage of albuminuria and renal injury in Dahl salt-sensitive rats on a high-salt diet: comparison with spontaneously hypertensive rats.

Our aim was to study the effects of high-salt diet on the genetics of albuminuria and renal injury in the Dahl salt-sensitive (SS) rat. We compared SS with salt-resistant spontaneously hypertensive rats (SHR) and with genetically related salt-sensitive stroke-prone SHR (SHRSP). Moreover, we performed genome-wide linkage analysis to identify quantitative trait loci (QTL) contributing to salt-induced renal injury in an F2 population derived from SS and SHR (n = 230). In response to high-salt diet SS and SHRSP developed a striking increase in systolic blood pressure, urinary albumin excretion (UAE), and renal damage indices compared with SHR. Both SHRSP and SS developed severe glomerulosclerosis, whereas microangiopathy, tubulointerstitial fibrosis, and inflammation were more pronounced in SHRSP. We detected two QTL with significant linkage to UAE on rat chromosomes (RNO) 6 and 19. Comparison with the recently identified salt-independent UAE QTL in young animals revealed that the UAE QTL on RNO6 is unique to high-salt conditions, whereas RNO19 plays a significant role during both low- and high-salt conditions. Some F2 animals demonstrated severe microangiopathy and tubulointerstitial injury, which exceeded the degree observed in the parental SS strain. Three loci demonstrated suggestive linkage to these phenotypes on RNO3, RNO5, and RNO20, whereas no linkage to glomerular damage was found. Further analyses at these loci indicated that the severity of renal injury was attributable to the SHR allele. Our data suggest that the SHR genetic background confers greater susceptibility for the development of microangiopathy and tubulointerstitial injury in salt-sensitive hypertension than the SS background.

Albuminuria↗

PubMed2004

Vascular endothelial growth factor serum level is strongly enhanced after burn injury and correlated with local and general tissue edema.

BACKGROUND: Burn associated local and general tissue edema is induced by local cell destruction and capillary leak syndrome. Vascular endothelial growth factor (VEGF) strongly enhances vascular permeability as well as angiogenesis. The principal aim of this study was to investigate the systemic release of VEGF and its kinetics after severe burn injury in humans. METHODS: Thirty-six burn patients and 42 healthy volunteers were enrolled in this study. Circulating VEGF serum levels were measured by enzyme-linked immunosorbent assay at days 1, 3, 7, 14, 21, 28 and 35. Burn surface, tissue edema, complications and outcome were evaluated. RESULTS: VEGF serum levels were significantly increased after burn injuries immediately after injury until wound closure. VEGF levels reached their maximum at day 14 and were 22-fold increased compared to VEGF levels of healthy controls. After wound closure VEGF levels normalized. Local and general tissue edema disappeared after VEGF serum level normalization. CONCLUSIONS: VEGF serum levels are immediately enhanced after burn trauma until wound closure. At the same time, a local and general tissue edema was detected. We may speculate, that specific blockers of VEGF may have beneficial effects on edema and edema-related complications in severe burn patients.

Adolescent↗

PubMed2004

Longterm conditions of mimicked weightlessness influences the cytoskeleton in thyroid cells.

Weightlessness influences the human immune and hormone system, reduces bone mass, leads to muscle atrophy and cardiac atrophy. Effects on control mechanisms for proliferation, programmed cell death and differentiation are well documented. The principal aim of this study was to investigate changes of the cytoskeleton in thyroid cells cultured in vector-averaged gravity under clinostat rotation. After 12 hours the formation of multicellular spheroids started. An increase of extracellular matrix proteins and beta 1-integrin was observed. Laser scanning confocal microscopy of ML-1 follicular thyroid carcinoma cells and normal thyroid HTU-5 cells immunostained with anti-cytokeratin to demonstrate these intermediate filaments revealed that cytokeratin filaments extended from centers, were thickened, coalesced and shortened as compared to control cells. Moreover, vimentin was highly disorganized. The vimentin network formed a coiled aggregate closely associated with the nucleus. Western blot analyses of talin, alpha- and beta-tubulin showed a clear increase of these proteins in cells cultured under simulated 0 g. Our data suggest that the effects of microgravity on cultured human thyroid cells are accompanied by noticeable functional cellular changes. Future studies to clarify the pathway that regulate the observed integrin activation and the mechanisms by which they function have to be performed.

Cell Differentiation↗

PubMed2004

Vascular endothelial growth factor inhibits programmed cell death of endothelial cells induced by clinorotation.

The principal aim of this study was to investigate short- and long-term effects of clinorotation on human endothelial cells (EA hy 926 cell line) using a three-dimensional random positioning machine. Moreover, the impact of vascular endothelial growth factor (VEGF) was addressed. Immediately, within one hour and after four and twenty-four hours an increase of apoptotic cells was detected. VEGF significantly inhibited the amount of apoptotic endothelial cells (EC). VEGF reduced the amount of fas-positive EC. Moreover, after 24 hours, proliferating EC grew in form of three-dimensional multicellular spheroids and also as monolayers. The initially formed spheroids (maximum diameter 3 mm) remained stable up to the 15th day of clinorotation. Some spheroids revealed tubular structures. In addition, a clear increase of extracellular matrix proteins such as osteopontin and fibronectin was measured. The three-dimensional clinostat represents an important tool for cell biological experiments. VEGF significantly attenuated the changes of endothelial cells induced by simulated weightlessness in a cell protective manner.

Apoptosis↗

PubMed2003

Effects of PTK787/ZK222584, a tyrosine kinase inhibitor, on the growth of a poorly differentiated thyroid carcinoma: an animal study.

The process of neoangiogenesis is induced by several mediators. Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis including thyroid carcinomas. The principal aim of this study was to test the hypothesis that inhibition of VEGF activity by PTK787/ZK222584 (PTK/ZK), a specific blocker of both VEGF-receptor tyrosine kinases, could inhibit the growth of a poorly differentiated thyroid cancer. Human follicular thyroid tumor xenografts were implanted sc into nude mice. Eight days following implantation, the animals were randomized into two groups (n = 10 each group). One group received PTK/ZK daily, and the other was treated with sodium chloride (control). Treatment was orally administered using a gastric tube. All animals were killed after 4 wk. Tumors, blood, and samples of other organs were taken for further examinations. Treatment with PTK/ZK induced a 41.4% reduction in tumor volumes. Necrosis of the tumors was detectable earlier in PTK/ZK-treated mice compared with controls. Immunohistochemistry revealed a significant decrease in neoangiogenesis in tumors of PTK/ZK-treated animals. Moreover, no compensatory overexpression of VEGF protein was detectable in the treated group. The compound was well tolerated by the animals without significant side effects on body weight or in general. These results showed that VEGF receptor blockade is a rational approach to the therapy of thyroid cancer. The combination of radioiodine or external radiation with VEGF receptor tyrosine kinase inhibitors might be a new option, especially for poorly differentiated thyroid cancers with limited or no response to conventional therapy.

Adenocarcinoma, Follicular↗

PubMed2003

Early onset albuminuria in Dahl rats is a polygenetic trait that is independent from salt loading.

The aim of the study was to characterize the genetic basis for the early onset of increased urinary albumin excretion (UAE) observed in the salt-sensitive Dahl rat (SS). We first characterized blood pressures and UAE values in adult SS compared with the spontaneously hypertensive rat (SHR) strain. Blood pressure measurements by radiotelemetry at 14 wk demonstrated similar spontaneous hypertension in both strains on a low-sodium diet containing 0.2% NaCl by weight, whereas UAE was markedly increased in SS compared with SHR (253.07 +/- 68.39 vs. 1.65 +/- 1.09 mg/24 h, P < 0.0001). Analysis of UAE in young animals of both strains fed a low-sodium diet demonstrated that UAE is elevated in SS as early as 4 wk of age (P < 0.0001), when ultrastructural evaluation of glomeruli by electron microscopy appears still normal. At 8 wk SS demonstrated a 280-fold elevated UAE compared with SHR (P < 0.0001). Consequently, to identify quantitative trait loci (QTLs) contributing to salt-independent early manifestation of increased UAE in the SS rat, we performed genome-wide linkage and QTL mapping analysis in a young F(2) population derived from the two contrasting strains. UAE was determined in 539 F(2) animals at 8 wk. We identified seven suggestive or significant UAE QTLs on rat chromosomes (RNO) RNO2, RNO6, RNO8, RNO9, RNO10, RNO11, and RNO19, accounting together for 34% of the overall variance of UAE in this F(2) population. Thus early onset albuminuria in the SS rat is under polygenetic influence and independent from salt loading.

Albuminuria↗

PubMed2003

Genetic loci contribute to the progression of vascular and cardiac hypertrophy in salt-sensitive spontaneous hypertension.

OBJECTIVE: The salt-sensitive Dahl rat and the spontaneously hypertensive rat develop comparable spontaneous hypertension on a low-salt diet, whereas only the salt-sensitive Dahl rat strain develops a striking increase in blood pressure and cardiovascular hypertrophy on a high-salt diet. We set out to identify quantitative trait loci (QTLs) contributing to the progression of salt-induced organ damage in hypertension by studying an F2 population derived from both strains. METHODS AND RESULTS: We determined systolic blood pressure (SBP), vascular aortic hypertrophy (AH), cardiac left ventricular (LV) hypertrophy (LVH), and LV fibrosis in 230 male F2-animals on a high-salt diet. A strong correlation between AH and LVH was found (r=0.58, P<0.0001), and genome-wide QTL mapping detected suggestive or significant QTLs in overlapping chromosomal fragments for AH and LVH on chromosomes 1, 3, and 19, respectively. A significant influence of SBP on the extent of LVH and AH was evident at all QTLs, although significant linkage to SBP (together with LVH) was only found on chromosome 9. No QTLs for LV fibrosis were detected. CONCLUSIONS: This study demonstrates a strong correlation between AH and LVH in salt-sensitive hypertension and identifies QTLs contributing to the progression of cardiovascular hypertrophy in this condition.

Animals↗

PubMed2003

Nephroprotective effects of the endothelin ET(A) receptor antagonist darusentan in salt-sensitive genetic hypertension.

We tested the effect of selective endothelin ET(A) receptor blockade on the development renal damage in the Sabra rat model of genetic salt-sensitivity. Animals from the salt-sensitive (SBH/y) and salt-resistant strains (SBN/y) were either salt-loaded with deoxycorticosterone acetate and salt (DOCA) or fed a normal diet. Additional salt-loaded groups were also treated with the selective ET(A) antagonist darusentan (DA). Salt-loading in SBH/y increased systolic blood pressure by 75 mm Hg and urinary albumin excretion 23-fold (P<0.0001). Darusentan attenuated the rise of systolic blood pressure (50%) and urinary albumin excretion (63%, P<0.01, respectively). Salt-loading in SBH/y was associated with significant increased osteopontin mRNA expression as well as glomerulosclerosis and tubulointerstitial damage in the kidney (P<0.05, respectively). This was either significantly reduced or normalized by darusentan (P<0.05, respectively). Thus, darusentan confers a significant renal protection in the Sabra model of salt-sensitive hypertension.

Albuminuria↗

PubMed2003

Renal damage is not improved by blockade of endothelin receptors in primary renin-dependent hypertension.

OBJECTIVE: Secondary activation of the renin-angiotensin system plays a major role in the progression of chronic nephropathies, and blockade of endothelin (ET) receptors has been shown to confer nephroprotection in experimental models of proteinuric renal disease. We tested the nephroprotective potential of selective endothelin A receptor (ETA) and non-selective ETA and endothelin B (ETA/B) receptor blockade in the TGR(mRen2)27 transgenic rat model with renin-dependent hypertension (Ren2). DESIGN: Ren2 animals were treated between 10 and 30 weeks of age with the selective ETA receptor antagonist darusentan (Ren2-ETA) and the ETA/B receptor antagonist Lu420627 (Ren2-ETA/B), and compared with transgene negative Sprague-Dawley (SD) controls. Since the elevated systolic blood pressure in Ren2 was not affected in either Ren2-ETA or Ren2-ETA/ETB, an additional Ren-2 group was treated with a non-antihypertensive dose of the angiotensin II type 1 receptor blocker eprosartan (Ren2-AT1). RESULTS: During the 20-week observation period 35% of untreated Ren2, 30% of Ren2-ETA/B, 50% of Ren2-ETA, and 83% of Ren2-AT1 animals survived compared with 100% of SD rats. Renal endothelin-1 mRNA expression and proteinuria (4.1-fold) were significantly elevated in Ren2 compared with SD rats (P < 0.05, respectively). Proteinuria was normalized to SD control levels in Ren2-AT1 (P < 0.05) but increased further in Ren2-ETA (7.7-fold) and Ren2-ETA/B (15-fold) (P < 0.05, respectively). Glomerulosclerosis, tubulointerstitial damage and renal osteopontin mRNA expression were reduced in Ren2-AT1 (P < 0.05, respectively) but remained unchanged or increased further in Ren2-ETA and Ren2-ETA/B compared with Ren2. CONCLUSION: ET receptor blockade fails to improve renal damage and mortality in primary renin-dependent hypertension.

Acrylates↗

PubMed2003

A major gene locus links early onset albuminuria with renal interstitial fibrosis in the MWF rat with polygenetic albuminuria.

The development of renal interstitial fibrosis (RIF) represents an important step in the progression of chronic proteinuric nephropathies. The Munich Wistar Frömter (MWF) rat represents a valuable model to study the progression in proteinuric renal disease. MWF animals demonstrate a significant increase of urinary albumin excretion (UAE) and RIF compared with the spontaneously hypertensive rat (SHR) with low UAE. The aim of this study was to analyze the genetic basis and the relation between UAE and RIF by genetic linkage and quantitative trait loci (QTL) mapping analysis. The authors generated a backcross population between MWF and SHR including 215 male animals. UAE was determined in young backcross animals at 8 wk, and at 14 and 24 wk of age, respectively. RIF was evaluated by Sirius red staining of kidney sections and quantified by computer-assisted image analysis at 24 wk. Total genome scan analysis identified in total eight QTL linked to UAE and a major locus on chromosome 6. At this locus, homozygosity for the MWF allele exhibited a strong effect on UAE levels (threefold elevation) and displayed significant linkage already at 8 wk (logarithm of odds [LOD] = 4.3) with increasing significance at 14 and 24 wk (LOD = 7.8 and 10.1, respectively). In addition, this was the only QTL that was linked to the amount of RIF (P = 0.0009, LOD = 2.4). These data establish a genetic link between early onset albuminuria and progression of RIF at the QTL on RNO6. This study demonstrates the power of genetic linkage analysis for the dissection of physiologic pathways involved in renal disease progression.

Albuminuria↗